Hdac inhibitor solid state forms

ABSTRACT

The present disclosure relates to the crystalline mesylate Form 1 salt of N-hydroxy 2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0 ]hex-3-yl}pyrimidine-5-carboxamide and methods of making the same. The crystalline mesylate Form 1 salt of N-hydroxy 2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide is useful in preparation of pharmaceutical compositions and dosage forms for the treatment of cancer, immune disorders and inflammation.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims benefit of U.S. Patent Application No.63/106,811 filed on Oct. 28, 2020 which is incorporated by reference inits entirety.

BACKGROUND OF THE INVENTION

The present disclosure relates to pharmaceutically acceptable salt formsof a histone deacetylase inhibitor compound and pharmaceuticalcompositions of said salt form, as well as the use of said compound inpharmaceutical compositions and medicine.

SUMMARY OF THE INVENTION

One embodiment provides a crystalline mesylate Form 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

One embodiment provides a crystalline mesylate Form 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideas characterized by an X-ray diffraction pattern reflection at a 2 thetavalue of 3.7°±0.3. One embodiment provides a crystalline mesylate Form 1salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideas characterized by an X-ray diffraction pattern reflection at a 2 thetavalue of 3.7°±0.3, and 14.9°±0.3. One embodiment provides a crystallinemesylate Form 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideas characterized by an X-ray diffraction pattern reflection at a 2 thetavalue of 3.7°±0.3, 7.5°±0.3, and 14.9°±0.3.

One embodiment provides a crystalline mesylate Form 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide,wherein the crystalline mesylate form 1 salt is characterized by atleast one X-ray diffraction pattern reflection selected from a 2 thetavalue of 3.7°±0.3, 7.5°±0.3, 14.9°±0.3, 17.3°±0.3, 19.7°±0.3, 22.5°±0.3,22.9°±0.3, or 30.1°±0.3. One embodiment provides a crystalline mesylateForm 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide,wherein the crystalline mesylate form 1 salt is characterized by atleast two X-ray diffraction pattern reflections selected from a 2 thetavalue of 3.7°±0.3, 7.5°±0.3, 14.9°±0.3, 17.3°±0.3, 19.7°±0.3, 22.5°±0.3,22.9°±0.3, or 30.1°±0.3. One embodiment provides a crystalline mesylateForm 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide,wherein the crystalline mesylate form 1 salt is characterized by atleast three X-ray diffraction pattern reflections selected from a 2theta value of 3.7°±0.3, 7.5°±0.3, 14.9°±0.3, 17.3°±0.3, 19.7°±0.3,22.5°±0.3, 22.9°±0.3, or 30.1°±0.3. One embodiment provides acrystalline mesylate Form 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide,wherein the crystalline mesylate form 1 salt is characterized by atleast four X-ray diffraction pattern reflections selected from a 2 thetavalue of 3.7°±0.3, 7.5°±0.3, 14.9°±0.3, 17.3°±0.3, 19.7°±0.3, 22.5°±0.3,22.9°±0.3, or 30.1°±0.3. One embodiment provides a crystalline mesylateForm 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide,wherein the crystalline mesylate form 1 salt is characterized by atleast five X-ray diffraction pattern reflections selected from a 2 thetavalue of 3.7°±0.3, 7.5°±0.3, 14.9°±0.3, 17.3°±0.3, 19.7°±0.3, 22.5°±0.3,22.9°±0.3, or 30.1°±0.3.

One embodiment provides a crystalline mesylate Form 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideexhibiting the X-ray powder diffraction pattern as shown in FIG. 1 .

One embodiment provides a crystalline mesylate Form 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideexhibiting the TGA pattern as shown in FIG. 3 .

One embodiment provides a crystalline mesylate Form 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamidewherein the DSC is characterized by a single exothermic event with anonset temperature at about 222.1° C.±5.0 (433 J/g) or an exothermic peakat 225.8° C.±5.0.

One embodiment provides a crystalline mesylate Form 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideexhibiting the DSC pattern as shown in FIG. 3 .

One embodiment provides an amorphous mesylate salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

One embodiment provides a solid form of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamidewherein the amount of other crystalline or amorphous forms is 5% (w/w)or less.

One embodiment provides a solid form of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide,wherein the solid form is substantially free of impurities.

One embodiment provides a solid form of N-hydroxy2-{6-[(6-fluoro-quinolinylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide,wherein the amount of impurities is 3% or less.

One embodiment provides a pharmaceutical composition comprising any oneof the compositions described herein, and one or more pharmaceuticallyacceptable excipients or carriers. One embodiment provides apharmaceutical composition further comprising one or more additionalactive pharmaceutical ingredient (API). One embodiment provides apharmaceutical composition, wherein the additional API isvalganciclovir.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The features of the invention are set forth with particularity in theappended claims. A better understanding of the features of the presentinvention will be obtained by reference to the following detaileddescription that sets forth illustrative embodiments, in which theprinciples of the invention are utilized, and the accompanying drawingsof which:

FIG. 1 shows the X-ray powder diffractogram of crystalline mesylate Form1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

FIG. 2 shows the ¹H NMR spectra of crystalline mesylate Form 1 salt ofN-hydroxy 2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

FIG. 3 shows the thermal gravimetric analysis pattern of crystallinemesylate Form 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo [3.1 .O]hex-3-yl}pyrimidine-5-carboxamide.

FIG. 4 shows the HPLC analysis of crystalline mesylate Form 1 salt ofN-hydroxy 2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

FIG. 5 shows the microscope image of crystalline mesylate Form 1 salt ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

FIG. 6 shows the GVS kinetic plot of crystalline mesylate Form 1 salt ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine

FIG. 7 shows the GVS isotherm plot of crystalline mesylate Form 1 saltof N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidinecarboxamide.

FIG. 8 shows the X-ray powder diffractogram of crystalline mesylate Form1 salt after GVS analysis of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

FIG. 9 shows the X-ray powder diffractogram of crystalline mesylate Form1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideafter storage under the indicated conditions.

FIG. 10 shows the HPLC analysis of crystalline mesylate Form 1 salt ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideafter storage under the indicated conditions.

FIG. 11 shows the X-ray powder diffractogram of the amorphous mesylatesalt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

FIG. 12 shows the TGA and DSC pattern of the amorphous mesylate salt ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

FIG. 13 shows the XRPD of crystalline mesylate Form 2 of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

FIG. 14 shows the TGA and DSC of crystalline mesylate Form 2 ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

FIG. 15 shows the GVS kinetic plot of crystalline mesylate Form 2 ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

FIG. 16 shows the GVS isotherm plot of crystalline mesylate Form 2 ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

FIG. 17 shows the XRPD of crystalline mesylate Form 3 of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine

FIG. 18 shows the TGA and DSC of crystalline mesylate Form 3 ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidinecarboxamide.

FIG. 19 shows the GVS kinetic plot of crystalline mesylate Form 3 ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyyrimidine-5-carboxamide.

FIG. 20 shows the GVS isotherm plot of crystalline mesylate Form 3 ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyyrimidine-5-carboxamide.

FIG. 21 shows the XRPD of crystalline mesylate Form 4 of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

FIG. 22 shows the TGA and DSC of crystalline mesylate Form 4 ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

FIG. 23 shows the GVS kinetic plot of crystalline mesylate Form 4 ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyyrimidine-5-carboxamide.

FIG. 24 shows the GVS isotherm plot of crystalline mesylate Form 4 ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyyrimidine-5-carboxamide.

FIG. 25 shows the XRPD of crystalline mesylate Form 5 of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

FIG. 26 shows the TGA and DSC of crystalline mesylate Form 5 ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

FIG. 27 shows the GVS kinetic plot of crystalline mesylate Form 5 ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyyrimidine-5-carboxamide.

FIG. 28 shows the GVS isotherm plot of crystalline mesylate Form 5 ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyyrimidine

FIG. 29 shows the X-ray powder diffractogram of crystalline mesylateForm 6 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyyrimidine-5-carboxamide.

FIG. 30 shows the TGA and DSC pattern of crystalline mesylate Form 6salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyyrimidine-5-carboxamide.

FIG. 31 shows the X-ray powder diffractogram of crystalline mesylateForm 7 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyyrimidine-5-carboxamide.

FIG. 32 shows the X-ray powder diffractogram of crystalline mesylateForm 8 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyyrimidine-5-carboxamide.

FIG. 33 shows the TGA and DSC pattern of crystalline mesylate Form 8salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyyrimidine-5-carboxamide.

FIG. 34 shows the X-ray powder diffractogram of crystalline mesylateForm 9 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyyrimidine-5-carboxamide.

FIG. 35 shows the TGA and DSC pattern of crystalline mesylate Form 9salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyyrimidine-5-carboxamide.

DETAILED DESCRIPTION OF THE INVENTION

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

Compounds that are histone deacetylase (HDAC) inhibitors have thepotential to provide therapeutically effective pharmaceuticalcompositions that would be expected to have beneficial and improvedpharmaceutical properties for the treatment of epigenetic relatedconditions or disorders such as cancer and other proliferativedisorders.

Discussed herein isN-hydroxy-2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideand referred to herein as Compound 1. Compound 1 is also known asnanatinostat, VRx-3996, or CHR-3996. It has been previously described inpatents and patent applications, e.g. U.S. Pat. No. 7,932,246 and U.S.patent application Ser. No. 15/959,482, each of which is incorporated byreference in their entirety.

As a selective inhibitor of HDAC, Compound 1 is useful in the treatmentof conditions in which HDAC has demonstrated a role in epigeneticregulation and pathology, such as cancer, immune disorders andinflammation. Two critical aspects in the development of Compound 1 as auseful therapy for such diseases and disorders are the discovery ofpractical methods for the preparation of Compound 1, and the discoveryof pharmaceutically acceptable forms of Compound 1 and pharmaceuticalcompositions comprising said forms.

Definitions

As used herein, the term “crystalline,” “highly crystalline,”“crystalline solid form,” or “highly crystalline solid form” refers to asolid form which is substantially free of any amorphous solid stateform. In some embodiments, the crystalline solid form is a single solidstate form, e.g. crystalline mesylate Form 1 salt. One embodimentprovides a composition wherein substantially free means less than about10% (w/w), less than about 9% (w/w), less than about 8% (w/w), less thanabout 7% (w/w), less than about 6% (w/w), less than about 5% (w/w), lessthan about 4.75% (w/w), less than about 4.5% (w/w), less than about4.25% (w/w), less than about 4% (w/w), less than about 3.75% (w/w), lessthan about 3.5% (w/w), less than about 3.25% (w/w), less than about 3%(w/w), less than about 2.75% (w/w), less than about 2.5% (w/w), lessthan about 2.25% (w/w), less than about 2% (w/w), less than about 1.75%(w/w), less than about 1.5% (w/w), less than about 1.25% (w/w), lessthan about 1% (w/w), less than about 0.9% (w/w), less than about 0.8%(w/w), less than about 0.7% (w/w), less than about 0.6% (w/w), less thanabout 0.5% (w/w), less than about 0.4% (w/w), less than about 0.3%(w/w), less than about 0.25% (w/w), less than about 0.20% (w/w), lessthan about 0.15% (w/w), less than about 0.1% (w/w), less than about0.08% (w/w), or less than about 0.05% (w/w). One embodiment provides acomposition wherein substantially free means an undetectable amount. Oneembodiment provides a composition wherein substantially free means lessthan about 5% (w/w), less than about 3% (w/w), less than about 1% (w/w),less than about 0.5% (w/w), or less than about 0.2% (w/w).

As used herein, the term “partially crystalline” or “partiallycrystalline material” refers to an ad-mixture of two or more solid stateforms. In some embodiments, partially crystalline refers to anad-mixture of an amorphous solid form and at least one crystalline solidform. Partially crystalline material is not amorphous.

In some embodiments, crystallinity of a solid form is determined byX-Ray Powder Diffraction (XRPD). In some embodiments, crystallinity of asolid form is determined by solid state NMR.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this invention belongs. All patents and publicationsreferred to herein are incorporated by reference.

As used in the specification and claims, the singular form “a”, “an” and“the” includes plural references unless the context clearly dictatesotherwise.

The term “hydrate” and “solvate” are meant to describe crystallineCompound 1 forms that include an amount of water or solvent, assupported by data derived from differential scanning calorimetry (DSC)experiments, thermogravimetric analysis (TGA) experiments, X-raydiffraction experiments, and/or the procedure for generating the solidcrystalline form. In some embodiments, a solvate crystalline form orhydrate crystalline form comprises at least 1.5%, 1.75%, 2.0%, 2.5%,3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0%, 15.0%, or 20.0% of thetotal weight of the sample as water, solvent, or a combination thereof,as determined by TGA. In some embodiments, a solvate crystalline form orhydrate crystalline form exhibits at least one DSC endotherm onsetbefore or within 30° C. of the boiling point of water or the solvent(s)used in the generation of the crystalline form. For example, a hydratecrystalline form may have a DSC endotherm onset at 108° C., with theendotherm peak positioned at 124° C.

Crystalline solid forms termed a “solvate,” or “hydrate” are not meantto be limiting. For example, a solvate or hydrate can comprise acombination of water and solvent in the crystalline solid form.

The term “type,” “form,” and “pattern” are meant to be usedinterchangeably and are meant to refer to a particular crystallinematerial with properties described herein. For example, “crystallinehydrate Type A,” “crystalline hydrate Form A,” and “XRPD Pattern A”refer to the same crystalline matter.

The term “about” when referring to a number or a numerical range meansthat the number or numerical range referred to is an approximationwithin experimental variability (or within statistical experimentalerror), and thus the number or numerical range, in some instances, willvary between 1% and 15% of the stated number or numerical range.

The term “substantially similar” as used herein means an analyticalspectrum, such as XRPD pattern, DSC thermogram, or TGA thermogram, whichresembles the reference spectrum to a great degree in both the peaklocations and peak intensity.

Characterization of Compounds and Solid State Forms

In one embodiment, the present invention provides solid state forms ofthe mesylate salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide. In one embodiment, thecrystalline forms are characterized by the interlattice plane intervalsdetermined by a X-ray powder diffraction (XRPD) diffractogram. Thediffractogram is typically represented by a diagram plotting theintensity of the peaks versus the location of the peaks, i.e.,diffraction angle 2Θ (two-theta) in degrees. The characteristic peaks ofa given compound can be selected according to the peak locations andtheir relative intensity to distinguish compounds and crystallinestructures from others. Amorphous solid state forms were alsocharacterized by XRPD. Amorphous solid state forms exhibit an absence ofinterlattice plane intervals.

Both crystalline and amorphous solid state forms were identified for themesylate salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.Amorphous solid state forms as described herein are specifically denotedas such.

Those skilled in the art recognize that the measurements of the XRD peaklocations and/or intensity for a given crystalline form of the samecompound will vary within a margin of error. The values of degree 2Θallow appropriate error margins. Typically, the error margins arerepresented by “±”. For example, the degree 2Θ of “8.716±0.3” denotes arange from 8.716+0.3, i.e., 9.016, to 8.716-0.3, i.e., 8.416. Dependingon the sample preparation techniques, the calibration techniques appliedto the instruments, human operational variation, and etc., those skilledin the art recognize that the margin of error for a XRD can be ±0.5;±0.4; ±0.3; ±0.2; ±0.1; ±0.05; or less. Additional details of themethods and equipment used for the XRD analysis are described in theExamples section.

In one embodiment, the crystalline forms are characterized byDifferential Scanning calorimetry (DSC) and Thermogravimetric Analysis(TGA). The DSC thermogram is typically expressed by a diagram plottingthe normalized heat flow in units of Watts/gram (“W/g”) versus themeasured sample temperature in degree Celsius (C). The DSC thermogram isgenerally evaluated for extrapolated onset and end (outset)temperatures, peak temperature, and heat of fusion. The single maximumvalue of a DSV thermogram is often used as the characteristic peak todistinguish one crystalline form from another crystalline form. The TGAthermogram is typically expressed by a diagram plotting the weight losspercentage (%) versus the measured sample temperature in degree C. Inthe figures disclosed herein, DSC and TGA thermograms have been plottedsharing an X axis (temperature), but have distinct Y axes of weight %and heat flow corresponding respectively to TGA and DSC measurements.

Those skilled in the art recognize that the measurements of the DSC andTGA thermograms for a given crystalline form of the same compound willvary within a margin of error. The values of a single maximum value,expressed in degree C., allow appropriate error margins. Typically, theerror margins are represented by “±”. For example, the single maximumvalue of “53.1° C.±10.0” denotes a range from 53.1° C.+10.0, i.e., 63.1°C., to about 53.1° C.−10.0, i.e., 43.1° C. Depending on the samplepreparation techniques, crystallization conditions, calibrationtechniques applied to the instruments, human operational variations, andetc., those skilled in the art recognize that the appropriate margin oferror for a single maximum value can be ±10.0; ±7.5; ±5.0; ±2.5; ±2;±1.5; ±1; ±0.5; or less for any of the powder diffraction reflectionsdescribed herein.

Crystalline mesylate Form 1 salt of N-Hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide

Provided herein is crystalline mesylate Form 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyyrimidine-5-carboxamide.

Provided herein is crystalline mesylate Form 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyyrimidine-5-carboxamideas characterized by an X-ray diffraction pattern reflection at a 2 thetavalue of 7.5°±0.3.

Provided herein is crystalline mesylate Form 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyyrimidine-5-carboxamideas characterized by an X-ray diffraction pattern reflection at a 2 thetavalue of 3. 7°±0.3, and 14.9°±0.3.

Provided herein is crystalline mesylate Form 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyyrimidine-5-carboxamideas characterized by an X-ray diffraction pattern reflection at a 2 thetavalue of 3. 7°±0.3, 7.5°±0.3, and 14.9°±0.3.

Provided herein is crystalline mesylate Form 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyyrimidine-5-carboxamide,wherein the crystalline mesylate Form 1 salt is characterized by atleast one X-ray diffraction pattern reflection selected from a 2 thetavalue of 3.7°±0.3, 7.5°±0.3, 14.9°±0.3, 17.3°±0.3, 19.7°±0.3, 22.5°±0.3,22.9°±0.3, and 30.1°±0.3. Another embodiment provides the crystallineform further characterized by at least two X-ray diffraction patternreflections selected from a 2 theta value of 3.7°±0.3, 7.5°±0.3,14.9°±0.3, 17.3°±0.3, 19.7°±0.3, 22.5°±0.3, 22.9°±0.3, and 30.1°±0.3.Another embodiment provides the crystalline form further characterizedby at least three X-ray diffraction pattern reflections selected from a2 theta value of 3.7°±0.3, 7.5°±0.3, 14.9°±0.3, 17.3°±0.3, 19.7°±0.3,22.5°±0.3, 22.9°±0.3, and 30.1°±0.3. Another embodiment provides thecrystalline form further characterized by at least four X-raydiffraction pattern reflections selected from a 2 theta value of3.7°±0.3, 7.5°±0.3, 14.9°±0.3, 17.3°±0.3, 19.7°±0.3, 22.5°±0.3,22.9°±0.3, and 30.1°±0.3. Another embodiment provides the crystallineform further characterized by at least five X-ray diffraction patternreflections selected from a 2 theta value of 3.7°±0.3, 7.5°±0.3,14.9°±0.3, 17.3°±0.3, 19.7°±0.3, 22.5°±0.3, 22.9°±0.3, and 30.1°±0.3.

Provided herein is crystalline mesylate Form 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide,wherein the crystalline mesylate Form 1 salt is characterized byexhibits an X-ray powder diffraction reflection at a 2-theta value of22.9°±0.3. In some embodiments, the crystalline form exhibits an X-raypowder diffraction reflection at a 2-theta value of 3.7°±0.3 and16.7°±0.3. In some embodiments, the crystalline form exhibits an X-raypowder diffraction reflection at a 2-theta value of 7.5°±0.3 and19.7°±0.3. In some embodiments, the crystalline form exhibits an X-raypowder diffraction reflection at a 2-theta value of 17.3°±0.3,23.4°±0.3, and 25.3°±0.3. In some embodiments, the crystalline formexhibits an X-ray powder diffraction reflection at a 2-theta value of14.9°±0.3, 22.5°±0.3, 23.1°±0.3, 24.0°±0.3, 24.2°±0.3, and 30.1°±0.3.

Provided herein is crystalline mesylate Form 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide,wherein the crystalline mesylate Form 1 salt is characterized by atleast one X-ray diffraction pattern reflection selected from a 2 thetavalue of 3.7°±0.3, 7.5°±0.3, 14.9°±0.3, 16.7°±0.3, 17.3°±0.3, 19.7°±0.3,22.5°±0.3, 22.9°±0.3, 23.1°±0.3, 23.4°±0.3, 24.0°±0.3, 24.2°±0.3,25.3°±0.3, and 30.1°±0.3. In some embodiments, the crystalline mesylateForm 1 salt is characterized by at least two X-ray diffraction patternreflections selected from a 2 theta value of 3.7°±0.3, 7.5°±0.3,14.9°±0.3, 16.7°±0.3, 17.3°±0.3, 19.7°±0.3, 22.5°±0.3, 22.9°±0.3,23.1°±0.3, 23.4°±0.3, 24.0°±0.3, 24.2°±0.3, 25.3°±0.3, and 30.1°±0.3. Insome embodiments, the crystalline mesylate Form 1 salt is characterizedby at least three X-ray diffraction pattern reflections selected from a2 theta value of 3.7°±0.3, 7.5°±0.3, 14.9°±0.3, 16.7°±0.3, 17.3°±0.3,19.7°±0.3, 22.5°±0.3, 22.9°±0.3, 23.1°±0.3, 23.4°±0.3, 24.0°±0.3,24.2°±0.3, 25.3°±0.3, and 30.1°±0.3. In some embodiments, thecrystalline mesylate Form 1 salt is characterized by at least four X-raydiffraction pattern reflections selected from a 2 theta value of3.7°±0.3, 7.5°±0.3, 14.9°±0.3, 16.7°±0.3, 17.3°±0.3, 19.7°±0.3,22.5°±0.3, 22.9°±0.3, 23.1°±0.3, 23.4°±0.3, 24.0°±0.3, 24.2°±0.3,25.3°±0.3, and 30.1°±0.3. In some embodiments, the crystalline mesylateForm 1 salt is characterized by at least five X-ray diffraction patternreflections selected from a 2 theta value of 3.7°±0.3, 7.5°±0.3,14.9°±0.3, 16.7°±0.3, 17.3°±0.3, 19.7°±0.3, 22.5°±0.3, 22.9°±0.3,23.1°±0.3, 23.4°±0.3, 24.0°±0.3, 24.2°±0.3, 25.3°±0.3, and 30.1°±0.3.

Provided herein is crystalline mesylate Form 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideexhibiting the X-ray powder diffraction pattern as shown in FIG. 1 .

Provided herein is crystalline mesylate Form 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-3-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideexhibiting the TGA pattern as shown in FIG. 3 . In some embodiments, thecrystalline form exhibits less than 0.5%±0.5 weight loss up to 225°C.±10.0 as determined by thermogravimetric analysis.

Provided herein is crystalline mesylate Form 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamidewherein the DSC is characterized by a single exothermic event with anonset temperature at 222.1° C. ±5.0 (433 J/g) and an exothermic peak at225.8° C.±5.0 as shown in FIG. 3 .

Provided herein is the crystalline mesylate Form 1 salt N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideor a pharmaceutically acceptable salt, solution or hydrate thereof,substantially free of impurities. In some embodiments, the compound issubstantially free of structurally related impurities. One embodimentprovides a composition wherein the amount of impurities is less than 1%(w/w). One embodiment provides a composition wherein the amount ofimpurities is less than 0.5% (w/w). One embodiment provides acomposition wherein the amount of impurities is less than 0.4% (w/w).One embodiment provides a composition wherein the amount of impuritiesis less than 0.3% (w/w). One embodiment provides a composition whereinthe amount of impurities is less than 0.25% (w/w). One embodimentprovides a composition wherein the amount of impurities is less than0.20% (w/w). One embodiment provides a composition wherein the amount ofimpurities is less than 0.15% (w/w). One embodiment provides acomposition wherein the amount of impurities is less than 0.10% (w/w).One embodiment provides a composition wherein the amount of impuritiesis less than 0.08% (w/w). One embodiment provides a composition whereinthe amount of impurities is less than 0.0 5% (w/w). One embodimentprovides a composition wherein the amount of impurities is not more than1% (w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.5% (w/w). One embodiment provides acomposition wherein the amount of impurities is not more than 0.4%(w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.3% (w/w). One embodiment provides acomposition wherein the amount of impurities is not more than 0.25%(w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.20% (w/w). One embodiment provides acomposition wherein the amount of impurities is not more than 0.15%(w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.10% (w/w). One embodiment provides acomposition wherein the amount of impurities is not more than 0.0 8%(w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.05% (w/w). One embodiment provides acomposition wherein the amount of impurities is not detectable.

One embodiment provides a composition wherein substantially free meansless than about 10% (w/w), less than about 9% (w/w), less than about 8%(w/w), less than about 7% (w/w), less than about 6% (w/w), less thanabout 5% (w/w), less than about 4.75% (w/w), less than about 4.5% (w/w),less than about 4.25% (w/w), less than about 4% (w/w), less than about3.75% (w/w), less than about 3.5% (w/w), less than about 3.25% (w/w),less than about 3% (w/w), less than about 2.75% (w/w), less than about2.5% (w/w), less than about 2.25% (w/w), less than about 2% (w/w), lessthan about 1.75% (w/w), less than about 1.5% (w/w), less than about1.25% (w/w), less than about 1% (w/w), less than about 0.9% (w/w), lessthan about 0.8% (w/w), less than about 0.7% (w/w), less than about 0.6%(w/w), less than about 0.5% (w/w), less than about 0.4% (w/w), less thanabout 0.3% (w/w), less than about 0.25% (w/w), less than about 0.20%(w/w), less than about 0.15% (w/w), less than about 0.1% (w/w), lessthan about 0.08% (w/w), or less than about 0.05% (w/w). One embodimentprovides a composition wherein substantially free means an undetectableamount. One embodiment provides a composition wherein substantially freemeans less than about 5% (w/w), less than about 3% (w/w), less thanabout 1% (w/w), less than about 0.5% (w/w), or less than about 0.2%(w/w).

Crystalline mesylate Form 2 salt of N-Hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide

Provided herein is crystalline mesylate Form 2 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

Provided herein is crystalline mesylate Form 2 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide,wherein the crystalline mesylate Form 2 salt is characterized byexhibits an X-ray powder diffraction reflection ata 2-theta value of14.6°±0.3. In some embodiments, the crystalline form exhibits an X-raypowder diffraction reflection at a 2-theta value of 24.3°±0.3 and26.9°±0.3. In some embodiments, the crystalline form exhibits an X-raypowder diffraction reflection at a 2-theta value of 14.8°±0.3, 18.4°±0.3and 19.5°±0.3. In some embodiments, the crystalline form exhibits anX-ray powder diffraction reflection at a 2-theta value of 16.4°±0.3,20.5°±0.3, 21.9°±0.3, 23.5°±0.3, and 41.8°±0.3.

Provided herein is crystalline mesylate Form 2 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide,wherein the crystalline mesylate Form 2 salt is characterized by atleast one X-ray diffraction pattern reflection selected from a 2 thetavalue of 14.6°±0.3, 14.8°±0.3, 16.4°±0.3, 18.4°±0.3, 19.5°±0.3,20.5°±0.3, 21.9°±0.3, 23.5°±0.3, 24.3°±0.3, 26.9°±0.3, and 41.8°±0.3. Insome embodiments, the crystalline mesylate Form 2 salt is characterizedby at least two X-ray diffraction pattern reflections selected from a 2theta value of 14.6°±0.3, 14.8°±0.3, 16.4°±0.3, 18.4°±0.3, 19.5°±0.3,20.5°±0.3, 21.9°±0.3, 23.5°±0.3, 24.3°±0.3, 26.9°±0.3, and 41.8°±0.3. Insome embodiments, the crystalline mesylate Form 2 salt is characterizedby at least three X-ray diffraction pattern reflections selected from a2 theta value of 14.6°±0.3, 14.8°±0.3, 16.4°±0.3, 18.4°±0.3, 19.5°±0.3,20.5°±0.3, 21.9°±0.3, 23.5°±0.3, 24.3°±0.3, 26.9°±0.3, and 41.8°±0.3. Insome embodiments, the crystalline mesylate Form 2 salt is characterizedby at least four X-ray diffraction pattern reflections selected from a 2theta value of 14.6°±0.3, 14.8°±0.3, 16.4°±0.3, 18.4°±0.3, 19.5°±0.3,20.5°±0.3, 21.9°±0.3, 23.5°±0.3, 24.3°±0.3, 26.9°±0.3, and 41.8°±0.3. Insome embodiments, the crystalline mesylate Form 2 salt is characterizedby at least five X-ray diffraction pattern reflections selected from a 2theta value of 14.6°±0.3, 14.8°±0.3, 16.4°±0.3, 18.4°±0.3, 19.5°±0.3,20.5°±0.3, 21.9°±0.3, 23.5°±0.3, 24.3°±0.3, 26.9°±0.3, and 41.8°±0.3.

Provided herein is crystalline mesylate Form 2 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideexhibiting the X-ray powder diffraction pattern as shown in FIG. 13 .

Provided herein is crystalline mesylate Form 2 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideexhibiting the TGA pattern as shown in FIG. 14 . In some embodiments,the crystalline form exhibits less than 3.7%±0.5 weight loss up to 170°C.±10.0 as determined by thermogravimetric analysis.

Provided herein is crystalline mesylate Form 2 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamidewherein the DSC is characterized by a single endothermic event with anonset temperature at 124.7° C. ±5.0 (239.6 J/g) and an endothermic peakat 144.2° C.±5.0 as shown in FIG. 14 .

Provided herein is the crystalline mesylate Form 2 salt N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideor a pharmaceutically acceptable salt, solution or hydrate thereof,substantially free of impurities. In some embodiments, the compound issubstantially free of structurally related impurities. One embodimentprovides a composition wherein the amount of impurities is less than 1%(w/w). One embodiment provides a composition wherein the amount ofimpurities is less than 0.5% (w/w). One embodiment provides acomposition wherein the amount of impurities is less than 0.4% (w/w).One embodiment provides a composition wherein the amount of impuritiesis less than 0.3% (w/w). One embodiment provides a composition whereinthe amount of impurities is less than 0.25% (w/w). One embodimentprovides a composition wherein the amount of impurities is less than0.20% (w/w). One embodiment provides a composition wherein the amount ofimpurities is less than 0.15% (w/w). One embodiment provides acomposition wherein the amount of impurities is less than 0.10% (w/w).One embodiment provides a composition wherein the amount of impuritiesis less than 0.08% (w/w). One embodiment provides a composition whereinthe amount of impurities is less than 0.05% (w/w). One embodimentprovides a composition wherein the amount of impurities is not more than1% (w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.5% (w/w). One embodiment provides acomposition wherein the amount of impurities is not more than 0.4%(w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.3% (w/w). One embodiment provides acomposition wherein the amount of impurities is not more than 0.25%(w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.20% (w/w). One embodiment provides acomposition wherein the amount of impurities is not more than 0.15%(w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.10% (w/w). One embodiment provides acomposition wherein the amount of impurities is not more than 0.08%(w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.05% (w/w). One embodiment provides acomposition wherein the amount of impurities is not detectable.

One embodiment provides a composition wherein substantially free meansless than about 10% (w/w), less than about 9% (w/w), less than about 8%(w/w), less than about 7% (w/w), less than about 6% (w/w), less thanabout 5% (w/w), less than about 4.75% (w/w), less than about 4.5% (w/w),less than about 4.25% (w/w), less than about 4% (w/w), less than about3.75% (w/w), less than about 3.5% (w/w), less than about 3.25% (w/w),less than about 3% (w/w), less than about 2.75% (w/w), less than about2.5% (w/w), less than about 2.25% (w/w), less than about 2% (w/w), lessthan about 1.75% (w/w), less than about 1.5% (w/w), less than about1.25% (w/w), less than about 1% (w/w), less than about 0.9% (w/w), lessthan about 0.8% (w/w), less than about 0.7% (w/w), less than about 0.6%(w/w), less than about 0.5% (w/w), less than about 0.4% (w/w), less thanabout 0.3% (w/w), less than about 0.25% (w/w), less than about 0.20%(w/w), less than about 0.15% (w/w), less than about 0.1% (w/w), lessthan about 0.08% (w/w), or less than about 0.05% (w/w). One embodimentprovides a composition wherein substantially free means an undetectableamount. One embodiment provides a composition wherein substantially freemeans less than about 5% (w/w), less than about 3% (w/w), less thanabout 1% (w/w), less than about 0.5% (w/w), or less than about 0.2%(w/w).

Crystalline mesylate Form 3 salt of N-Hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide

Provided herein is crystalline mesylate Form 3 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

Provided herein is crystalline mesylate Form 3 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide,wherein the crystalline mesylate Form 3 salt is characterized byexhibits an X-ray powder diffraction reflection at a 2-theta value of9.5°±0.3. In some embodiments, the crystalline form exhibits an X-raypowder diffraction reflection at a 2-theta value of 10.3°±0.3 and19.4°±0.3. In some embodiments, the crystalline form exhibits an X-raypowder diffraction reflection at a 2-theta value of 14.8°±0.3 and24.8°±0.3. In some embodiments, the crystalline form exhibits an X-raypowder diffraction reflection at a 2-theta value of 6.3°±0.3, 16.5°±0.3,°±0.3, and 27.2°±0.3.

Provided herein is crystalline mesylate Form 3 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide,wherein the crystalline mesylate Form 3 salt is characterized by atleast one X-ray diffraction pattern reflection selected from a 2 thetavalue of 6.3°±0.3, 9.5°±0.3, 10.3°±0.3, 14.8°±0.3, 16.5°±0.3, 19.4°±0.3,°±0.3, 24.8°±0.3, and 27.2°±0.3. In some embodiments, the crystallinemesylate Form 3 salt is characterized by at least two X-ray diffractionpattern reflections selected from a 2 theta value of 6.3°±0.3, 9.5°±0.3,10.3°±0.3, 14.8°±0.3, 16.5°±0.3, 19.4°±0.3, °±0.3, 24.8°±0.3, and27.2°±0.3. In some embodiments, the crystalline mesylate Form 3 salt ischaracterized by at least three X-ray diffraction pattern reflectionsselected from a 2 theta value of 6.3°±0.3, 9.5°±0.3, 10.3°±0.3,14.8°±0.3, 16.5°±0.3, 19.4°±0.3, 23 .3°±0.3, 24.8°±0.3, and 27.2°±0.3.In some embodiments, the crystalline mesylate Form 3 salt ischaracterized by at least four X-ray diffraction pattern reflectionsselected from a 2 theta value of 6.3°±0.3, 9.5°±0.3, 10.3°±0.3,14.8°±0.3, 16.5°±0.3, 19.4°±0.3, °±0.3, 24.8°±0.3, and 27.2°±0.3. Insome embodiments, the crystalline mesylate Form 3 salt is characterizedby at least five X-ray diffraction pattern reflections selected from a 2theta value of 6.3°±0.3, 9.5°±0.3, 10.3°±0.3, 14.8°±0.3, 16.5°±0.3,19.4°±0.3, °±0.3, 24.8°±0.3, and 27.2°±0.3.

Provided herein is crystalline mesylate Form 3 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideexhibiting the X-ray powder diffraction pattern as shown in FIG. 17 .

Provided herein is crystalline mesylate Form 3 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideexhibiting the TGA pattern as shown in FIG. 18 . In some embodiments,the crystalline form exhibits less than 28.8%±0.5 weight loss up to 135°C.±10.0 as determined by thermogravimetric analysis.

Provided herein is crystalline mesylate Form 3 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamidewherein the DSC is characterized by an endothermic event with an onsettemperature at 48.2° C.±5.0 (62 J/g) and an endothermic peak at 51.9°C.±5.0; and an endothermic event with an onset temperature at 113.0°C.±5.0 (59 J/g) and an endothermic peak at 113.2° C.±5.0 as shown inFIG. 18 .

Provided herein is the crystalline mesylate Form 3 salt N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideor a pharmaceutically acceptable salt, solution or hydrate thereof,substantially free of impurities. In some embodiments, the compound issubstantially free of structurally related impurities. One embodimentprovides a composition wherein the amount of impurities is less than 1%(w/w). One embodiment provides a composition wherein the amount ofimpurities is less than 0.5% (w/w). One embodiment provides acomposition wherein the amount of impurities is less than 0.4% (w/w).One embodiment provides a composition wherein the amount of impuritiesis less than 0.3% (w/w). One embodiment provides a composition whereinthe amount of impurities is less than 0.25% (w/w). One embodimentprovides a composition wherein the amount of impurities is less than0.20% (w/w). One embodiment provides a composition wherein the amount ofimpurities is less than 0.15% (w/w). One embodiment provides acomposition wherein the amount of impurities is less than 0.10% (w/w).One embodiment provides a composition wherein the amount of impuritiesis less than 0.08% (w/w). One embodiment provides a composition whereinthe amount of impurities is less than 0.05% (w/w). One embodimentprovides a composition wherein the amount of impurities is not more than1% (w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.5% (w/w). One embodiment provides acomposition wherein the amount of impurities is not more than 0.4%(w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.3% (w/w). One embodiment provides acomposition wherein the amount of impurities is not more than 0.25%(w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.20% (w/w). One embodiment provides acomposition wherein the amount of impurities is not more than 0.15%(w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.10% (w/w). One embodiment provides acomposition wherein the amount of impurities is not more than 0.08%(w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.05% (w/w). One embodiment provides acomposition wherein the amount of impurities is not detectable.

One embodiment provides a composition wherein substantially free meansless than about 10% (w/w), less than about 9% (w/w), less than about 8%(w/w), less than about 7% (w/w), less than about 6% (w/w), less thanabout 5% (w/w), less than about 4.75% (w/w), less than about 4.5% (w/w),less than about 4.25% (w/w), less than about 4% (w/w), less than about3.75% (w/w), less than about 3.5% (w/w), less than about 3.25% (w/w),less than about 3% (w/w), less than about 2.75% (w/w), less than about2.5% (w/w), less than about 2.25% (w/w), less than about 2% (w/w), lessthan about 1.75% (w/w), less than about 1.5% (w/w), less than about1.25% (w/w), less than about 1% (w/w), less than about 0.9% (w/w), lessthan about 0.8% (w/w), less than about 0.7% (w/w), less than about 0.6%(w/w), less than about 0.5% (w/w), less than about 0.4% (w/w), less thanabout 0.3% (w/w), less than about 0.25% (w/w), less than about 0.20%(w/w), less than about 0.15% (w/w), less than about 0.1% (w/w), lessthan about 0.08% (w/w), or less than about 0.05% (w/w). One embodimentprovides a composition wherein substantially free means an undetectableamount. One embodiment provides a composition wherein substantially freemeans less than about 5% (w/w), less than about 3% (w/w), less thanabout 1% (w/w), less than about 0.5% (w/w), or less than about 0.2%(w/w).

Crystalline mesylate Form 4 salt of N-Hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide

Provided herein is crystalline mesylate Form 4 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyyrimidine-5-carboxamide.

Provided herein is crystalline mesylate Form 4 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide,wherein the crystalline mesylate Form 4 salt is characterized byexhibits an X-ray powder diffraction reflection at a 2-theta value of 3.5°±0.3. In some embodiments, the crystalline form exhibits an X-raypowder diffraction reflection at a 2-theta value of 10.3°±0.3,17.2°±0.3, and 17.7°±0.3. In some embodiments, the crystalline formexhibits an X-ray powder diffraction reflection at a 2-theta value of22.4°±0.3, 24.7°±0.3, and 26.4°±0.3.

Provided herein is crystalline mesylate Form 4 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide,wherein the crystalline mesylate Form 4 salt is characterized by atleast one X-ray diffraction pattern reflection selected from a 2 thetavalue of 3.5°±0.3, 10.3°±0.3, 17.2°±0.3, 17.7°±0.3, 22.4°±0.3,24.7°±0.3, and 26.4°±0.3. In some embodiments, the crystalline mesylateForm 4 salt is characterized by at least two X-ray diffraction patternreflections selected from a 2 theta value of 3.5°±0.3, 10.3°±0.3,17.2°±0.3, 17.7°±0.3, 22.4°±0.3, 24.7°±0.3, and 26.4°±0.3. In someembodiments, the crystalline mesylate Form 4 salt is characterized by atleast three X-ray diffraction pattern reflections selected from a 2theta value of 3.5°±0.3, 10.3°±0.3, 17.2°±0.3, 17.7°±0.3, 22.4°±0.3,24.7°±0.3, and 26.4°±0.3. In some embodiments, the crystalline mesylateForm 4 salt is characterized by at least four X-ray diffraction patternreflections selected from a 2 theta value of 3.5°±0.3, 10.3°±0.3,17.2°±0.3, 17.7°±0.3, 22.4°±0.3, 24.7°±0.3, and 26.4°±0.3. In someembodiments, the crystalline mesylate Form 4 salt is characterized by atleast five X-ray diffraction pattern reflections selected from a 2 thetavalue of 3.5°±0.3, 10.3°±0.3, 17.2°±0.3, 17.7°±0.3, 22.4°±0.3,24.7°±0.3, and 26.4°±0.3.

Provided herein is crystalline mesylate Form 4 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideexhibiting the X-ray powder diffraction pattern as shown in FIG. 21 .

Provided herein is crystalline mesylate Form 4 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideexhibiting the TGA pattern as shown in FIG. 22 . In some embodiments,the crystalline form exhibits less than 9.6%±0.5 weight loss up to 92°C.±10.0 as determined by thermogravimetric analysis.

Provided herein is crystalline mesylate Form 4 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamidewherein the DSC is characterized by a single endothermic event with anonset temperature at 51.0° C. ±5.0 (269 J/g) and an endothermic peak at77.3° C.±5.0 as shown in FIG. 22 .

Provided herein is the crystalline mesylate Form 4 salt N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideor a pharmaceutically acceptable salt, solution or hydrate thereof,substantially free of impurities. In some embodiments, the compound issubstantially free of structurally related impurities. One embodimentprovides a composition wherein the amount of impurities is less than 1%(w/w). One embodiment provides a composition wherein the amount ofimpurities is less than 0.5% (w/w). One embodiment provides acomposition wherein the amount of impurities is less than 0.4% (w/w).One embodiment provides a composition wherein the amount of impuritiesis less than 0.3% (w/w). One embodiment provides a composition whereinthe amount of impurities is less than 0.25% (w/w). One embodimentprovides a composition wherein the amount of impurities is less than0.20% (w/w). One embodiment provides a composition wherein the amount ofimpurities is less than 0.15% (w/w). One embodiment provides acomposition wherein the amount of impurities is less than 0.10% (w/w).One embodiment provides a composition wherein the amount of impuritiesis less than 0.08% (w/w). One embodiment provides a composition whereinthe amount of impurities is less than 0.05% (w/w). One embodimentprovides a composition wherein the amount of impurities is not more than1% (w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.5% (w/w). One embodiment provides acomposition wherein the amount of impurities is not more than 0.4%(w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.3% (w/w). One embodiment provides acomposition wherein the amount of impurities is not more than 0.25%(w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.20% (w/w). One embodiment provides acomposition wherein the amount of impurities is not more than 0.15%(w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.10% (w/w). One embodiment provides acomposition wherein the amount of impurities is not more than 0.08%(w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.05% (w/w). One embodiment provides acomposition wherein the amount of impurities is not detectable.

One embodiment provides a composition wherein substantially free meansless than about 10% (w/w), less than about 9% (w/w), less than about 8%(w/w), less than about 7% (w/w), less than about 6% (w/w), less thanabout 5% (w/w), less than about 4.75% (w/w), less than about 4.5% (w/w),less than about 4.25% (w/w), less than about 4% (w/w), less than about3.75% (w/w), less than about 3.5% (w/w), less than about 3.25% (w/w),less than about 3% (w/w), less than about 2.75% (w/w), less than about2.5% (w/w), less than about 2.25% (w/w), less than about 2% (w/w), lessthan about 1.75% (w/w), less than about 1.5% (w/w), less than about1.25% (w/w), less than about 1% (w/w), less than about 0.9% (w/w), lessthan about 0.8% (w/w), less than about 0.7% (w/w), less than about 0.6%(w/w), less than about 0.5% (w/w), less than about 0.4% (w/w), less thanabout 0.3% (w/w), less than about 0.25% (w/w), less than about 0.20%(w/w), less than about 0.15% (w/w), less than about 0.1% (w/w), lessthan about 0.08% (w/w), or less than about 0.05% (w/w). One embodimentprovides a composition wherein substantially free means an undetectableamount. One embodiment provides a composition wherein substantially freemeans less than about 5% (w/w), less than about 3% (w/w), less thanabout 1% (w/w), less than about 0.5% (w/w), or less than about 0.2%(w/w).

Crystalline mesylate Form 5 salt of N-Hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide

Provided herein is crystalline mesylate Form 5 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

Provided herein is crystalline mesylate Form 5 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide,wherein the crystalline mesylate Form 5 salt is characterized byexhibits an X-ray powder diffraction reflection ata 2-theta value of20.7°±0.3. In some embodiments, the crystalline form exhibits an X-raypowder diffraction reflection at a 2-theta value of 15.7°±0.3, 16.8°±0.3and 18.0°±0.3. In some embodiments, the crystalline form exhibits anX-ray powder diffraction reflection at a 2-theta value of 27.4°±0.3 and34.6°±0.3. In some embodiments, the crystalline form exhibits an X-raypowder diffraction reflection at a 2-theta value of 21.5°±0.3,24.3°±0.3, 33.9°±0.3, 36.7°±0.3, and 40.9°±0.3.

Provided herein is crystalline mesylate Form 5 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide,wherein the crystalline mesylate Form 5 salt is characterized by atleast one X-ray diffraction pattern reflection selected from a 2 thetavalue of 15.7°±0.3, 16.8°±0.3, 18.0°±0.3, 20.7°±0.3, 21.5°±0.3,24.3°±0.3, 27.4°±0.3, 33.9°±0.3, 34.6°±0.3, 36.7°±0.3, and 40.9°±0.3. Insome embodiments, the crystalline mesylate Form 5 salt is characterizedby at least two X-ray diffraction pattern reflections selected from a 2theta value of 15.7°±0.3, 16.8°±0.3, 18.0°±0.3, 20.7°±0.3, 21.5°±0.3,24.3°±0.3, 27.4°±0.3, 33.9°±0.3, 34.6°±0.3, 36.7°±0.3, and 40.9°±0.3. Insome embodiments, the crystalline mesylate Form 5 salt is characterizedby at least three X-ray diffraction pattern reflections selected from a2 theta value of 15.7°±0.3, 16.8°±0.3, 18.0°±0.3, 20.7°±0.3, 21.5°±0.3,24.3°±0.3, 27.4°±0.3, 33.9°±0.3, 34.6°±0.3, 36.7°±0.3, and 40.9°±0.3. Insome embodiments, the crystalline mesylate Form 5 salt is characterizedby at least four X-ray diffraction pattern reflections selected from a 2theta value of 15.7°±0.3, 16.8°±0.3, 18.0°±0.3, 20.7°±0.3, 21.5°±0.3,24.3°±0.3, 27.4°±0.3, 33.9°±0.3, 34.6°±0.3, 36.7°±0.3, and 40.9°±0.3. Insome embodiments, the crystalline mesylate Form 5 salt is characterizedby at least five X-ray diffraction pattern reflections selected from a 2theta value of 15.7°±0.3, 16.8°±0.3, 18.0°±0.3, 20.7°±0.3, 21.5°±0.3,24.3°±0.3, 27.4°±0.3, 33 .9°±0.3, 34.6°±0.3, 36.7°±0.3, and 40.9°±0.3.

Provided herein is crystalline mesylate Form 5 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideexhibiting the X-ray powder diffraction pattern as shown in FIG. 25 .

Provided herein is crystalline mesylate Form 5 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideexhibiting the TGA pattern as shown in FIG. 26 . In some embodiments,the crystalline form exhibits less than 5.9%±0.5 weight loss up to 130°C.±10.0 as determined by thermogravimetric analysis.

Provided herein is crystalline mesylate Form 5 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamidewherein the DSC is characterized by an endothermic event with an onsettemperature at 28.4° C.±5.0 (6 J/g) and an endothermic peak at 38.1°C.±5.0; an endothermic event with an onset temperature at 56.8° C.±5.0(52 J/g) and an endothermic peak at 93.2° C.±5.0; an endothermic eventwith an onset temperature at 152.3° C.±5.0 (6 J/g) and an endothermicpeak at 161° C.±5.0; and an exothermic event with an onset temperatureat 163.3° C.±5.0 (14 J/g) and an exothermic peak at 166.5° C.±5.0 asshown in FIG. 26 .

Provided herein is the crystalline mesylate Form 5 salt N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideor a pharmaceutically acceptable salt, solution or hydrate thereof,substantially free of impurities. In some embodiments, the compound issubstantially free of structurally related impurities. One embodimentprovides a composition wherein the amount of impurities is less than 1%(w/w). One embodiment provides a composition wherein the amount ofimpurities is less than 0.5% (w/w). One embodiment provides acomposition wherein the amount of impurities is less than 0.4% (w/w).One embodiment provides a composition wherein the amount of impuritiesis less than 0.3% (w/w). One embodiment provides a composition whereinthe amount of impurities is less than 0.25% (w/w). One embodimentprovides a composition wherein the amount of impurities is less than0.20% (w/w). One embodiment provides a composition wherein the amount ofimpurities is less than 0.15% (w/w). One embodiment provides acomposition wherein the amount of impurities is less than 0.10% (w/w).One embodiment provides a composition wherein the amount of impuritiesis less than 0.08% (w/w). One embodiment provides a composition whereinthe amount of impurities is less than 0.05% (w/w). One embodimentprovides a composition wherein the amount of impurities is not more than1% (w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.5% (w/w). One embodiment provides acomposition wherein the amount of impurities is not more than 0.4%(w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.3% (w/w). One embodiment provides acomposition wherein the amount of impurities is not more than 0.25%(w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.20% (w/w). One embodiment provides acomposition wherein the amount of impurities is not more than 0.15%(w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.10% (w/w). One embodiment provides acomposition wherein the amount of impurities is not more than 0.08%(w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.05% (w/w). One embodiment provides acomposition wherein the amount of impurities is not detectable.

One embodiment provides a composition wherein substantially free meansless than about 10% (w/w), less than about 9% (w/w), less than about 8%(w/w), less than about 7% (w/w), less than about 6% (w/w), less thanabout 5% (w/w), less than about 4.75% (w/w), less than about 4.5% (w/w),less than about 4.25% (w/w), less than about 4% (w/w), less than about3.75% (w/w), less than about 3.5% (w/w), less than about 3.25% (w/w),less than about 3% (w/w), less than about 2.75% (w/w), less than about2.5% (w/w), less than about 2.25% (w/w), less than about 2% (w/w), lessthan about 1.75% (w/w), less than about 1.5% (w/w), less than about1.25% (w/w), less than about 1% (w/w), less than about 0.9% (w/w), lessthan about 0.8% (w/w), less than about 0.7% (w/w), less than about 0.6%(w/w), less than about 0.5% (w/w), less than about 0.4% (w/w), less thanabout 0.3% (w/w), less than about 0.25% (w/w), less than about 0.20%(w/w), less than about 0.15% (w/w), less than about 0.1% (w/w), lessthan about 0.08% (w/w), or less than about 0.05% (w/w). One embodimentprovides a composition wherein substantially free means an undetectableamount. One embodiment provides a composition wherein substantially freemeans less than about 5% (w/w), less than about 3% (w/w), less thanabout 1% (w/w), less than about 0.5% (w/w), or less than about 0.2

Crystalline mesylate Form 6 salt of N-Hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide

Provided herein is crystalline mesylate Form 6 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

Provided herein is crystalline mesylate Form 6 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide,wherein the crystalline mesylate Form 6 salt is characterized byexhibits an X-ray powder diffraction reflection ata 2-theta value of22.9°±0.3. In some embodiments, the crystalline form exhibits an X-raypowder diffraction reflection at a 2-theta value of 6.7°±0.3 and16.2°±0.3. In some embodiments, the crystalline form exhibits an X-raypowder diffraction reflection at a 2-theta value of 15.7°±0.3,20.7°±0.3, and 25.9°±0.3. In some embodiments, the crystalline formexhibits an X-ray powder diffraction reflection at a 2-theta value of4.3°±0.3, 17.2°±0.3, 25.4°±0.3, and 27.4°±0.3.

Provided herein is crystalline mesylate Form 6 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide,wherein the crystalline mesylate Form 6 salt is characterized by atleast one X-ray diffraction pattern reflection selected from a 2 thetavalue of 4.3°±0.3, 6.7°±0.3, 15.7°±0.3, 16.2°±0.3, 17.2°±0.3, 20.7°±0.3,22.9°±0.3, 25.4°±0.3, 25.9°±0.3, and 27.4°±0.3. In some embodiments, thecrystalline mesylate Form 6 salt is characterized by at least two X-raydiffraction pattern reflections selected from a 2 theta value of4.3°±0.3, 6.7°±0.3, 15.7°±0.3, 16.2°±0.3, 17.2°±0.3, 20.7°±0.3,22.9°±0.3, 25.4°±0.3, 25.9°±0.3, and 27.4°±0.3. In some embodiments, thecrystalline mesylate Form 6 salt is characterized by at least threeX-ray diffraction pattern reflections selected from a 2 theta value of4.3°±0.3, 6.7°±0.3, 15.7°±0.3, 16.2°±0.3, 17.2°±0.3, 20.7°±0.3,22.9°±0.3, 25.4°±0.3, 25.9°±0.3, and 27.4°±0.3. In some embodiments, thecrystalline mesylate Form 6 salt is characterized by at least four X-raydiffraction pattern reflections selected from a 2 theta value of4.3°±0.3, 6.7°±0.3, 15.7°±0.3, 16.2°±0.3, 17.2°±0.3, 20.7°±0.3,22.9°±0.3, 25.4°±0.3, 25.9°±0.3, and 27.4°±0.3. In some embodiments, thecrystalline mesylate Form 6 salt is characterized by at least five X-raydiffraction pattern reflections selected from a 2 theta value of4.3°±0.3, 6.7°±0.3, 15.7°±0.3, 16.2°±0.3, 17.2°±0.3, 20.7°±0.3,22.9°±0.3, 25.4°±0.3, 25.9°±0.3, and 27.4°±0.3.

Provided herein is crystalline mesylate Form 6 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideexhibiting the X-ray powder diffraction pattern as shown in FIG. 29 .

Provided herein is crystalline mesylate Form 6 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideexhibiting the TGA pattern as shown in FIG. 30 . In some embodiments,the crystalline form exhibits less than 9.0%±0.5 weight loss up to 113°C.±10.0 as determined by thermogravimetric analysis.

Provided herein is crystalline mesylate Form 6 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamidewherein the DSC is characterized by a single endothermic event with anonset temperature at 84.7° C. ±5.0 (79.8 J/g) and an endothermic peak at92.1° C.±5.0 as shown in FIG. 30 .

Provided herein is the crystalline mesylate Form 6 salt N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideor a pharmaceutically acceptable salt, solution or hydrate thereof,substantially free of impurities. In some embodiments, the compound issubstantially free of structurally related impurities. One embodimentprovides a composition wherein the amount of impurities is less than 1%(w/w). One embodiment provides a composition wherein the amount ofimpurities is less than 0.5% (w/w). One embodiment provides acomposition wherein the amount of impurities is less than 0.4% (w/w).One embodiment provides a composition wherein the amount of impuritiesis less than 0.3% (w/w). One embodiment provides a composition whereinthe amount of impurities is less than 0.25% (w/w). One embodimentprovides a composition wherein the amount of impurities is less than0.20% (w/w). One embodiment provides a composition wherein the amount ofimpurities is less than 0.15% (w/w). One embodiment provides acomposition wherein the amount of impurities is less than 0.10% (w/w).One embodiment provides a composition wherein the amount of impuritiesis less than 0.08% (w/w). One embodiment provides a composition whereinthe amount of impurities is less than 0.05% (w/w). One embodimentprovides a composition wherein the amount of impurities is not more than1% (w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.5% (w/w). One embodiment provides acomposition wherein the amount of impurities is not more than 0.4%(w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.3% (w/w). One embodiment provides acomposition wherein the amount of impurities is not more than 0.25%(w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.20% (w/w). One embodiment provides acomposition wherein the amount of impurities is not more than 0.15%(w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.10% (w/w). One embodiment provides acomposition wherein the amount of impurities is not more than 0.08%(w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.05% (w/w). One embodiment provides acomposition wherein the amount of impurities is not detectable.

One embodiment provides a composition wherein substantially free meansless than about 10% (w/w), less than about 9% (w/w), less than about 8%(w/w), less than about 7% (w/w), less than about 6% (w/w), less thanabout 5% (w/w), less than about 4.75% (w/w), less than about 4.5% (w/w),less than about 4.25% (w/w), less than about 4% (w/w), less than about3.75% (w/w), less than about 3.5% (w/w), less than about 3.25% (w/w),less than about 3% (w/w), less than about2.75% (w/w), less thanabout2.5% (w/w), less than about2.25% (w/w), less than about 2% (w/w),less than about 1.75% (w/w), less than about 1.5% (w/w), less than about1.25% (w/w), less than about 1% (w/w), less than about 0.9% (w/w), lessthan about 0.8% (w/w), less than about 0.7% (w/w), less than about 0.6%(w/w), less than about 0.5% (w/w), less than about 0.4% (w/w), less thanabout 0.3% (w/w), less than about 0.25% (w/w), less than about 0.20%(w/w), less than about 0.15% (w/w), less than about 0.1% (w/w), lessthan about 0.08% (w/w), or less than about 0.05% (w/w). One embodimentprovides a composition wherein substantially free means an undetectableamount. One embodiment provides a composition wherein substantially freemeans less than about 5% (w/w), less than about 3% (w/w), less thanabout 1% (w/w), less than about 0.5% (w/w), or less than about 0.2%(w/w).

One embodiment provides a composition wherein substantially free meansless than about 10% (w/w), less than about 9% (w/w), less than about 8%(w/w), less than about 7% (w/w), less than about 6% (w/w), less thanabout 5% (w/w), less than about 4.75% (w/w), less than about 4.5% (w/w),less than about 4.25% (w/w), less than about 4% (w/w), less than about3.75% (w/w), less than about 3.5% (w/w), less than about 3.25% (w/w),less than about 3% (w/w), less than about2.75% (w/w), less thanabout2.5% (w/w), less than about2.25% (w/w), less than about 2% (w/w),less than about 1.75% (w/w), less than about 1.5% (w/w), less than about1.25% (w/w), less than about 1% (w/w), less than about 0.9% (w/w), lessthan about 0.8% (w/w), less than about 0.7% (w/w), less than about 0.6%(w/w), less than about 0.5% (w/w), less than about 0.4% (w/w), less thanabout 0.3% (w/w), less than about 0.25% (w/w), less than about 0.20%(w/w), less than about 0.15% (w/w), less than about 0.1% (w/w), lessthan about 0.08% (w/w), or less than about 0.05% (w/w). One embodimentprovides a composition wherein substantially free means an undetectableamount. One embodiment provides a composition wherein substantially freemeans less than about 5% (w/w), less than about 3% (w/w), less thanabout 1% (w/w), less than about 0.5% (w/w), or less than about 0.2%(w/w).

Crystalline mesylate Form 7 salt of N-Hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide

Provided herein is crystalline mesylate Form 7 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

Provided herein is crystalline mesylate Form 7 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide,wherein the crystalline mesylate Form 7 salt is characterized byexhibits an X-ray powder diffraction reflection ata 2-theta value of16.3°±0.3. In some embodiments, the crystalline form exhibits an X-raypowder diffraction reflection at a 2-theta value of 20.6°±0.3 and22.9°±0.3. In some embodiments, the crystalline form exhibits an X-raypowder diffraction reflection at a 2-theta value of 15.6°±0.3 and21.4°±0.3. In some embodiments, the crystalline form exhibits an X-raypowder diffraction reflection at a 2-theta value of 6.7°±0.3, 10.4°±0.3,°±0.3, and 25.2°±0.3.

Provided herein is crystalline mesylate Form 7 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide,wherein the crystalline mesylate Form 7 salt is characterized by atleast one X-ray diffraction pattern reflection selected from a 2 thetavalue of 6.7°±0.3, 10.4°±0.3, 15.6°±0.3, 16.3°±0.3, 20.6°±0.3,21.4°±0.3, 22.9°±0.3, °±0.3, and 25.2°±0.3. In some embodiments, thecrystalline mesylate Form 7 salt is characterized by at least two X-raydiffraction pattern reflections selected from a 2 theta value of6.7°±0.3, 10.4°±0.3, 15.6°±0.3, 16.3°±0.3, 20.6°±0.3, 21.4°±0.3,22.9°±0.3, °±0.3, and 25.2°±0.3. In some embodiments, the crystallinemesylate Form 7 salt is characterized by at least three X-raydiffraction pattern reflections selected from a 2 theta value of6.7°±0.3, 10.4°±0.3, 15.6°±0.3, 16.3°±0.3, 20.6°±0.3, 21.4°±0.3,22.9°±0.3, °±0.3, and 25.2°±0.3. In some embodiments, the crystallinemesylate Form 7 salt is characterized by at least four X-ray diffractionpattern reflections selected from a 2 theta value of 6.7°±0.3,10.4°±0.3, 15.6°±0.3, 16.3°±0.3, 20.6°±0.3, 21.4°±0.3, 22.9°±0.3, °±0.3,and 25.2°±0.3. In some embodiments, the crystalline mesylate Form 7 saltis characterized by at least five X-ray diffraction pattern reflectionsselected from a 2 theta value of 6.7°±0.3, 10.4°±0.3, 15.6°±0.3,16.3°±0.3, 20.6°±0.3, 21.4°±0.3, 22.9°±0.3, °±0.3, and 25.2°±0.3.

Provided herein is crystalline mesylate Form 7 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideexhibiting the X-ray powder diffraction pattern as shown in FIG. 31 .

Provided herein is the crystalline mesylate Form 7 salt N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideor a pharmaceutically acceptable salt, solution or hydrate thereof,substantially free of impurities. In some embodiments, the compound issubstantially free of structurally related impurities. One embodimentprovides a composition wherein the amount of impurities is less than 1%(w/w). One embodiment provides a composition wherein the amount ofimpurities is less than 0.5% (w/w). One embodiment provides acomposition wherein the amount of impurities is less than 0.4% (w/w).One embodiment provides a composition wherein the amount of impuritiesis less than 0.3% (w/w). One embodiment provides a composition whereinthe amount of impurities is less than 0.25% (w/w). One embodimentprovides a composition wherein the amount of impurities is less than0.20% (w/w). One embodiment provides a composition wherein the amount ofimpurities is less than 0.15% (w/w). One embodiment provides acomposition wherein the amount of impurities is less than 0.10% (w/w).One embodiment provides a composition wherein the amount of impuritiesis less than 0.08% (w/w). One embodiment provides a composition whereinthe amount of impurities is less than 0.05% (w/w). One embodimentprovides a composition wherein the amount of impurities is not more than1% (w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.5% (w/w). One embodiment provides acomposition wherein the amount of impurities is not more than 0.4%(w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.3% (w/w). One embodiment provides acomposition wherein the amount of impurities is not more than 0.25%(w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.20% (w/w). One embodiment provides acomposition wherein the amount of impurities is not more than 0.15%(w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.10% (w/w). One embodiment provides acomposition wherein the amount of impurities is not more than 0.08%(w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.05% (w/w). One embodiment provides acomposition wherein the amount of impurities is not detectable.

One embodiment provides a composition wherein substantially free meansless than about 10% (w/w), less than about 9% (w/w), less than about 8%(w/w), less than about 7% (w/w), less than about 6% (w/w), less thanabout 5% (w/w), less than about 4.75% (w/w), less than about 4.5% (w/w),less than about 4.25% (w/w), less than about 4% (w/w), less than about3.75% (w/w), less than about 3.5% (w/w), less than about 3.25% (w/w),less than about 3% (w/w), less than about 2.75% (w/w), less than about2.5% (w/w), less than about 2.25% (w/w), less than about 2% (w/w), lessthan about 1.75% (w/w), less than about 1.5% (w/w), less than about1.25% (w/w), less than about 1% (w/w), less than about 0.9% (w/w), lessthan about 0.8% (w/w), less than about 0.7% (w/w), less than about 0.6%(w/w), less than about 0.5% (w/w), less than about 0.4% (w/w), less thanabout 0.3% (w/w), less than about 0.25% (w/w), less than about 0.20%(w/w), less than about 0.15% (w/w), less than about 0.1% (w/w), lessthan about 0.08% (w/w), or less than about 0.05% (w/w). One embodimentprovides a composition wherein substantially free means an undetectableamount. One embodiment provides a composition wherein substantially freemeans less than about 5% (w/w), less than about 3% (w/w), less thanabout 1% (w/w), less than about 0.5% (w/w), or less than about 0.2%(w/w).

Crystalline mesylate Form 8 salt of N-Hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide

Provided herein is crystalline mesylate Form 8 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

Provided herein is crystalline mesylate Form 8 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide,wherein the crystalline mesylate Form 8 salt is characterized byexhibits an X-ray powder diffraction reflection at a 2-theta value of4.4°±0.3. In some embodiments, the crystalline form exhibits an X-raypowder diffraction reflection at a 2-theta value of 6.8°±0.3 and16.2°±0.3. In some embodiments, the crystalline form exhibits an X-raypowder diffraction reflection at a 2-theta value of 8.7°±0.3 and14.1°±0.3. In some embodiments, the crystalline form exhibits an X-raypowder diffraction reflection at a 2-theta value of 13.1°±0.3,18.2°±0.3, 20.4°±0.3, and 20.8°±0.3.

Provided herein is crystalline mesylate Form 8 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide,wherein the crystalline mesylate Form 8 salt is characterized by atleast one X-ray diffraction pattern reflection selected from a 2 thetavalue of 4.4°±0.3, 6.8°±0.3, 8.7°±0.3, 13.1°±0.3, 14.1°±0.3, 16.2°±0.3,18.2°±0.3, 20.4°±0.3, and 20.8°±0.3. In some embodiments, thecrystalline mesylate Form 8 salt is characterized by at least two X-raydiffraction pattern reflections selected from a 2 theta value of4.4°±0.3, 6.8°±0.3, 8.7°±0.3, 13.1°±0.3, 14.1°±0.3, 16.2°±0.3,18.2°±0.3, 20.4°±0.3, and 20.8°±0.3. In some embodiments, thecrystalline mesylate Form 8 salt is characterized by at least threeX-ray diffraction pattern reflections selected from a 2 theta value of4.4°±0.3, 6.8°±0.3, 8.7°±0.3, 13.1°±0.3, 14.1°±0.3, 16.2°±0.3,18.2°±0.3, 20.4°±0.3, and 20.8°±0.3. In some embodiments, thecrystalline mesylate Form 8 salt is characterized by at least four X-raydiffraction pattern reflections selected from a 2 theta value of4.4°±0.3, 6.8°±0.3, 8.7°±0.3, 13.1°±0.3, 14.1°±0.3, 16.2°±0.3,18.2°±0.3, 20.4°±0.3, and 20.8°±0.3. In some embodiments, thecrystalline mesylate Form 8 salt is characterized by at least five X-raydiffraction pattern reflections selected from a 2 theta value of4.4°±0.3, 6.8°±0.3, 8.7°±0.3, 13.1°±0.3, 14.1°±0.3, 16.2°±0.3,18.2°±0.3, 20.4°±0.3, and 20.8°±0.3.

Provided herein is crystalline mesylate Form 8 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideexhibiting the X-ray powder diffraction pattern as shown in FIG. 32 .

Provided herein is crystalline mesylate Form 8 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideexhibiting the TGA pattern as shown in FIG. 33 . In some embodiments,the crystalline form exhibits less than 12.2%±0.5 weight loss up to 134°C.±10.0 as determined by thermogravimetric analysis.

Provided herein is crystalline mesylate Form 8 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamidewherein the DSC is characterized by a single endothermic event with anonset temperature at 98.8° C. ±5.0 (108.1 J/g) and an endothermic peakat 98.9° C.±5.0 as shown in FIG. 33 .

Provided herein is the crystalline mesylate Form 8 salt N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideor a pharmaceutically acceptable salt, solution or hydrate thereof,substantially free of impurities. In some embodiments, the compound issubstantially free of structurally related impurities. One embodimentprovides a composition wherein the amount of impurities is less than 1%(w/w). One embodiment provides a composition wherein the amount ofimpurities is less than 0.5% (w/w). One embodiment provides acomposition wherein the amount of impurities is less than 0.4% (w/w).One embodiment provides a composition wherein the amount of impuritiesis less than 0.3% (w/w). One embodiment provides a composition whereinthe amount of impurities is less than 0.25% (w/w). One embodimentprovides a composition wherein the amount of impurities is less than0.20% (w/w). One embodiment provides a composition wherein the amount ofimpurities is less than 0.15% (w/w). One embodiment provides acomposition wherein the amount of impurities is less than 0.10% (w/w).One embodiment provides a composition wherein the amount of impuritiesis less than 0.08% (w/w). One embodiment provides a composition whereinthe amount of impurities is less than 0.05% (w/w). One embodimentprovides a composition wherein the amount of impurities is not more than1% (w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.5% (w/w). One embodiment provides acomposition wherein the amount of impurities is not more than 0.4%(w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.3% (w/w). One embodiment provides acomposition wherein the amount of impurities is not more than 0.25%(w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.20% (w/w). One embodiment provides acomposition wherein the amount of impurities is not more than 0.15%(w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.10% (w/w). One embodiment provides acomposition wherein the amount of impurities is not more than 0.08%(w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.05% (w/w). One embodiment provides acomposition wherein the amount of impurities is not detectable.

One embodiment provides a composition wherein substantially free meansless than about 10% (w/w), less than about 9% (w/w), less than about 8%(w/w), less than about 7% (w/w), less than about 6% (w/w), less thanabout 5% (w/w), less than about 4.75% (w/w), less than about 4.5% (w/w),less than about 4.25% (w/w), less than about 4% (w/w), less than about3.75% (w/w), less than about 3.5% (w/w), less than about 3.25% (w/w),less than about 3% (w/w), less than about 2.75% (w/w), less than about2.5% (w/w), less than about 2.25% (w/w), less than about 2% (w/w), lessthan about 1.75% (w/w), less than about 1.5% (w/w), less than about1.25% (w/w), less than about 1% (w/w), less than about 0.9% (w/w), lessthan about 0.8% (w/w), less than about 0.7% (w/w), less than about 0.6%(w/w), less than about 0.5% (w/w), less than about 0.4% (w/w), less thanabout 0.3% (w/w), less than about 0.25% (w/w), less than about 0.20%(w/w), less than about 0.15% (w/w), less than about 0.1% (w/w), lessthan about 0.08% (w/w), or less than about 0.05% (w/w). One embodimentprovides a composition wherein substantially free means an undetectableamount. One embodiment provides a composition wherein substantially freemeans less than about 5% (w/w), less than about 3% (w/w), less thanabout 1% (w/w), less than about 0.5% (w/w), or less than about 0.2%(w/w).

Crystalline mesylate Form 9 salt of N-Hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide

Provided herein is crystalline mesylate Form 9 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

Provided herein is crystalline mesylate Form 9 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide,wherein the crystalline mesylate Form 9 salt is characterized byexhibits an X-ray powder diffraction reflection ata 2-theta value of17.2°±0.3. In some embodiments, the crystalline form exhibits an X-raypowder diffraction reflection at a 2-theta value of 4.2°±0.3 and8.4°±0.3. In some embodiments, the crystalline form exhibits an X-raypowder diffraction reflection at a 2-theta value of 8.6°±0.3 and15.0°±0.3. In some embodiments, the crystalline form exhibits an X-raypowder diffraction reflection at a 2-theta value of 22.2°±0.3 and24.1°±0.3.

Provided herein is crystalline mesylate Form 9 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide,wherein the crystalline mesylate Form 9 salt is characterized by atleast one X-ray diffraction pattern reflection selected from a 2 thetavalue of 4.2°±0.3, 8.4°±0.3, 8.6°±0.3, 15.0°±0.3, 17.2°±0.3, 22.2°±0.3and 24.1°±0.3. In some embodiments, the crystalline mesylate Form 9 saltis characterized by at least two X-ray diffraction pattern reflectionsselected from a 2 theta value of 4.2°±0.3, 8.4°±0.3, 8.6°±0.3,15.0°±0.3, 17.2°±0.3, 22.2°±0.3 and 24.1°±0.3. In some embodiments, thecrystalline mesylate Form 9 salt is characterized by at least threeX-ray diffraction pattern reflections selected from a 2 theta value of4.2°±0.3, 8.4°±0.3, 8.6°±0.3, 15.0°±0.3, 17.2°±0.3, 22.2°±0.3 and24.1°±0.3. In some embodiments, the crystalline mesylate Form 9 salt ischaracterized by at least four X-ray diffraction pattern reflectionsselected from a 2 theta value of 4.2°±0.3, 8.4°±0.3, 8.6°±0.3,15.0°±0.3, 17.2°±0.3, 22.2°±0.3 and 24.1°±0.3. In some embodiments, thecrystalline mesylate Form 9 salt is characterized by at least five X-raydiffraction pattern reflections selected from a 2 theta value of4.2°±0.3, 8.4°±0.3, 8.6°±0.3, 15.0°±0.3, 17.2°±0.3, 22.2°±0.3 and24.1°±0.3.

Provided herein is crystalline mesylate Form 9 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideexhibiting the X-ray powder diffraction pattern as shown in FIG. 34 .

Provided herein is crystalline mesylate Form 9 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideexhibiting the TGA pattern as shown in FIG. 35 . In some embodiments,the crystalline form exhibits less than 41.2%±0.5 weight loss up to 247°C.±10.0 as determined by thermogravimetric analysis.

Provided herein is crystalline mesylate Form 9 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamidewherein the DSC is characterized by an endothermic event with an onsettemperature at 78.2° C.±5.0 (57.7 J/g) and an endothermic peak at 91.1°C.±5.0 as shown in FIG. 35 .

Provided herein is the crystalline mesylate Form 9 salt N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideor a pharmaceutically acceptable salt, solution or hydrate thereof,substantially free of impurities. In some embodiments, the compound issubstantially free of structurally related impurities. One embodimentprovides a composition wherein the amount of impurities is less than 1%(w/w). One embodiment provides a composition wherein the amount ofimpurities is less than 0.5% (w/w). One embodiment provides acomposition wherein the amount of impurities is less than 0.4% (w/w).One embodiment provides a composition wherein the amount of impuritiesis less than 0.3% (w/w). One embodiment provides a composition whereinthe amount of impurities is less than 0.25% (w/w). One embodimentprovides a composition wherein the amount of impurities is less than0.20% (w/w). One embodiment provides a composition wherein the amount ofimpurities is less than 0.15% (w/w). One embodiment provides acomposition wherein the amount of impurities is less than 0.10% (w/w).One embodiment provides a composition wherein the amount of impuritiesis less than 0.08% (w/w). One embodiment provides a composition whereinthe amount of impurities is less than 0.05% (w/w). One embodimentprovides a composition wherein the amount of impurities is not more than1% (w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.5% (w/w). One embodiment provides acomposition wherein the amount of impurities is not more than 0.4%(w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.3% (w/w). One embodiment provides acomposition wherein the amount of impurities is not more than 0.25%(w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.20% (w/w). One embodiment provides acomposition wherein the amount of impurities is not more than 0.15%(w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.10% (w/w). One embodiment provides acomposition wherein the amount of impurities is not more than 0.08%(w/w). One embodiment provides a composition wherein the amount ofimpurities is not more than 0.05% (w/w). One embodiment provides acomposition wherein the amount of impurities is not detectable.

One embodiment provides a composition wherein substantially free meansless than about 10% (w/w), less than about 9% (w/w), less than about 8%(w/w), less than about 7% (w/w), less than about 6% (w/w), less thanabout 5% (w/w), less than about 4.75% (w/w), less than about 4.5% (w/w),less than about 4.25% (w/w), less than about 4% (w/w), less than about3.75% (w/w), less than about 3.5% (w/w), less than about 3.25% (w/w),less than about 3% (w/w), less than about 2.75% (w/w), less than about2.5% (w/w), less than about 2.25% (w/w), less than about 2% (w/w), lessthan about 1.75% (w/w), less than about 1.5% (w/w), less than about1.25% (w/w), less than about 1% (w/w), less than about 0.9% (w/w), lessthan about 0.8% (w/w), less than about 0.7% (w/w), less than about 0.6%(w/w), less than about 0.5% (w/w), less than about 0.4% (w/w), less thanabout 0.3% (w/w), less than about 0.25% (w/w), less than about 0.20%(w/w), less than about 0.15% (w/w), less than about 0.1% (w/w), lessthan about 0.08% (w/w), or less than about 0.05% (w/w). One embodimentprovides a composition wherein substantially free means an undetectableamount. One embodiment provides a composition wherein substantially freemeans less than about 5% (w/w), less than about 3% (w/w), less thanabout 1% (w/w), less than about 0.5% (w/w), or less than about 0.2%(w/w).

Pharmaceutical Compositions

Provided herein is a pharmaceutical composition comprising anycrystalline mesylate salt Forms 1-9 of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideor combinations thereof, and one or more pharmaceutically acceptableexcipients or carriers. In various embodiments, the pharmaceuticalcomposition further comprises at least one pharmaceutically acceptablevehicle, carrier, diluent, or excipient, or a mixture thereof. In someembodiments, provided herein is a pharmaceutical composition comprisingany crystalline mesylate salt Forms 1-9 of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideor combinations thereof, one or more pharmaceutically acceptableexcipients or carriers and one or more additional active pharmaceuticalingredients (API). In some embodiments, the additional API isvalganciclovir.

Provided herein is a pharmaceutical composition comprising crystallinemesylate Form 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide,and one or more pharmaceutically acceptable excipients or carriers. Invarious embodiments, the pharmaceutical composition further comprises atleast one pharmaceutically acceptable vehicle, carrier, diluent, orexcipient, or a mixture thereof. Provided herein is a pharmaceuticalcomposition comprising crystalline mesylate Form 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide,one or more pharmaceutically acceptable excipients or carriers, and oneor more additional active pharmaceutical ingredients (API). In someembodiments, the additional API is valganciclovir.

One embodiment provides a pharmaceutical composition comprisingcrystalline mesylate Form 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideas characterized by an X-ray diffraction pattern reflection at a 2 thetavalue of 7.5, and one or more pharmaceutically acceptable excipients orcarriers.

One embodiment provides a pharmaceutical composition comprisingcrystalline mesylate Form 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideas characterized by an X-ray diffraction pattern reflection ata 2 thetavalue of 3.7, and 14.9, and one or more pharmaceutically acceptableexcipients or carriers.

One embodiment provides a pharmaceutical composition comprisingcrystalline mesylate Form 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideas characterized by an X-ray diffraction pattern reflection at a 2 thetavalue of 3.7, 7.5, and 14.9, and one or more pharmaceutically acceptableexcipients or carriers.

One embodiment provides a pharmaceutical composition comprisingcrystalline mesylate Form 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideas characterized by at least one X-ray diffraction pattern reflectionselected from a 2 theta value of 3.7, 7.5, 14.9, 17.3, 19.7, 22.5, 22.9,or 30.1, and one or more pharmaceutically acceptable excipients orcarriers.

One embodiment provides a pharmaceutical composition comprisingcrystalline mesylate Form 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideas characterized by at least two X-ray diffraction pattern reflectionsselected from a 2 theta value of 3.7, 7.5, 14.9, 17.3, 19.7, 22.5, 22.9,or 30.1, and one or more pharmaceutically acceptable excipients orcarriers.

One embodiment provides a pharmaceutical composition comprisingcrystalline mesylate Form 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideas characterized by at least three X-ray diffraction pattern reflectionsselected from a 2 theta value of 3.7, 7.5, 14.9, 17.3, 19.7, 22.5, 22.9,or 30.1, and one or more pharmaceutically acceptable excipients orcarriers.

One embodiment provides a pharmaceutical composition comprisingcrystalline mesylate Form 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideas characterized by at least four X-ray diffraction pattern reflectionsselected from a 2 theta value of 3.7, 7.5, 14.9, 17.3, 19.7, 22.5, 22.9,or 30.1, and one or more pharmaceutically acceptable excipients orcarriers.

One embodiment provides a pharmaceutical composition comprisingcrystalline mesylate Form 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideas characterized by at least five X-ray diffraction pattern reflectionsselected from a 2 theta value of 3.7, 7.5, 14.9, 17.3, 19.7, 22.5, 22.9,or 30.1, and one or more pharmaceutically acceptable excipients orcarriers.

One embodiment provides a pharmaceutical composition comprisingcrystalline mesylate Form 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideexhibiting the X-ray powder diffraction pattern as shown in FIG. 1 , andone or more pharmaceutically acceptable excipients or carriers.

One embodiment provides a pharmaceutical composition comprisingcrystalline mesylate Form 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideexhibiting the TGA pattern as shown in FIG. 3 , and one or morepharmaceutically acceptable excipients or carriers.

One embodiment provides a pharmaceutical composition comprisingcrystalline mesylate Form 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamidewherein the DSC is characterized by a single endothermic event with anonset temperature at about 222.1° C. (433 J/g), and one or morepharmaceutically acceptable excipients or carriers.

The pharmaceutical compositions provided herein may be administered atonce, or multiple times at intervals of time. It is understood that theprecise dosage and duration of treatment may vary with the age, weight,and condition of the patient being treated, and may be determinedempirically using known testing protocols or by extrapolation from invivo or in vitro test or diagnostic data. It is further understood thatfor any particular individual, specific dosage regimens should beadjusted over time according to the individual need and the professionaljudgment of the person administering or supervising the administrationof the formulations.

Treatment dosages generally may be titrated to optimize safety andefficacy. Typically, dosage-effect relationships from in vitro studiesinitially can provide useful guidance on the proper doses for patientadministration. Studies in animal models also generally may be used forguidance regarding effective dosages for treatment in accordance withthe present disclosure. In terms of treatment protocols, it should beappreciated that the dosage to be administered will depend on severalfactors, including the particular agent that is administered, the routeadministered, the condition of the particular patient, etc.Determination of these parameters is well within the skill of the art.These considerations, as well as effective formulations andadministration procedures are well known in the art and are described instandard textbooks. One embodiment provides a method of treating EpsteinBar Virus Associated Lymphoid Malignancies in a patient need thereof,comprising administering to the patient a pharmaceutical compositioncomprising a solid state form of a mesylate slat of Compound 1. In someembodiments, the solid state form of the mesylate salt of Compound 1 isthe amorphous form. In some embodiments, the solid state form of themesylate salt of Compound 1 is any one of crystalline Forms 1-9. In someembodiments, the solid state form of the mesylate salt of Compound 1 iscrystalline Form 1. In some embodiments, the method comprisesadministering the solid state form of Compound 1 in combination with valganciclovir.

The pharmaceutical compositions provided herein are formulated invarious dosage forms for oral administration. These dosage forms can beprepared according to conventional methods and techniques known to thoseskilled in the art (see, Remington: The Science and Practice ofPharmacy, Loyd V., Jr, Allen, Ed., Pharmaceutical Press.: New York,N.Y., 2002; Vol. 22).

As used herein, oral administration also include buccal, lingual, andsublingual administration. Suitable oral dosage forms include, but arenot limited to, tablets, capsules, pills, troches, lozenges, pastilles,cachets, pellets, medicated chewing gum, granules, orally disintegratingtablets, dispersible tablets, bulk powders, and effervescent ornon-effervescent powders or granules. In addition to the activeingredient(s), the pharmaceutical compositions may contain one or morepharmaceutically acceptable carriers or excipients, including, but notlimited to, binders, fillers, diluents, disintegrants, wetting agents,lubricants, glidants, coloring agents, dye-migration inhibitors,sweetening agents, and flavoring agents. In some embodiments, the oraldosage form is a tablet, capsule, or pill. In further embodiments, theoral dosage form is a liquid, tablet for oral suspension or packet ofpowder to be dissolved in a beverage.

In further embodiments, the pharmaceutical compositions provided hereinmay be provided as compressed tablets, tablet triturates, chewablelozenges, rapidly dissolving tablets, multiple compressed tablets, orenteric-coating tablets, sugar-coated, or film-coated tablets.Enteric-coated tablets are compressed tablets coated with substancesthat resist the action of stomach acid but dissolve or disintegrate inthe intestine, thus protecting the active ingredients from the acidicenvironment of the stomach.

The tablet dosage forms may be prepared from the active ingredient inpowdered, crystalline, or granular forms, alone or in combination withone or more carriers or excipients described herein, including binders,disintegrants, controlled-release polymers, lubricants, diluents, and/orcolorants. Flavoring and sweetening agents are especially useful in theformation of chewable tablets and lozenges.

The pharmaceutical compositions provided herein may be provided as softor hard capsules, which can be made from gelatin, methylcellulose,starch, or calcium alginate. The hard gelatin capsule, also known as thedry-filled capsule, consists of two sections, one slipping over theother, thus completely enclosing the active ingredient. The soft elasticcapsule is a soft, globular shell, such as a gelatin shell, which isplasticized by the addition of glycerin, sorbitol, or a similar polyol.The liquid, semisolid, and solid dosage forms provided herein may beencapsulated in a capsule. Suitable liquid and semisolid dosage formsinclude solutions and suspensions in propylene carbonate, vegetableoils, or triglycerides.

The term “therapeutically effective amount” or “effective amount” is anamount sufficient to effect beneficial or desired clinical results. Aneffective amount can be administered in one or more administrations. Aneffective amount is typically sufficient to palliate, ameliorate,stabilize, reverse, slow or delay the progression of the disease state.

The examples and preparations provided below further illustrate andexemplify the salt forms of the present disclosure and methods ofpreparing such salt forms. It is to be understood that the scope of thepresent disclosure is not limited in any way by the scope of thefollowing examples and preparations.

EXAMPLES

The present disclosure is further illustrated by the following examples,which should not be construed as limiting in any way. The experimentalprocedures to generate the data shown are discussed in more detailbelow. The disclosure has been described in an illustrative manner, andit is to be understood that the terminology used is intended to be inthe nature of description rather than of limitation.

General Experimental, Instrument, and Methodology Details X-ray PowderDiffraction Bruker AXS D8 Advance

XRPD diffractograms were collected on a Bruker D8 diffractometer usingCu Kα radiation (40 kV, 40 mA) and a θ-2θ goniometer fitted with a Gemonochromator. The incident beam passes through a 2.0 mm divergence slitfollowed by a 0.2 mm anti-scatter slit and knife edge. The diffractedbeam passes through an 8.0 mm receiving slit with 2.5° Soller slitsfollowed by the Lynxeye Detector. The software used for data collectionand analysis was Diffrac Plus XRD Commander and Diffrac Plus EVArespectively.

Samples were run under ambient conditions as flat plate specimens usingpowder as received. The sample was prepared on a polished,zero-background (510) silicon wafer by gently pressing onto the flatsurface or packed into a cut cavity. The sample was rotated in its ownplane.

The details of the collection method are:

Angular range: 2 to 42° 2θ; Step size: 0.05° 2θ; Collection time: 0.5s/step (total collection

PANalytical Empyrean

XRPD diffractograms were collected on a PANalytical Empyreandiffractometer using Cu Kα radiation (45 kV, 40 mA) in transmissiongeometry. A 0.5° slit, 4 mm mask and 0.04 rad Soller slits with afocusing mirror were used on the incident beam. A PIXcel3D detector,placed on the diffracted beam, was fitted with a receiving slit and 0.04rad Soller slits. The software used for data collection was X′Pert DataCollector using X′Pert Operator Interface. The data were analyzed andpresented using Diffrac Plus EVA or HighScore Plus.

Samples were prepared and analyzed in a metal well-plate in transmissionmode. X-ray transparent film was used between the metal sheets on themetal well-plate and powders (approximately 1—2 mg) were used asreceived. The scan mode for the metal plate used the gonio scan axis.The details of the standard screening data collection method are:Angular range: 2.5 to 32.0° 2θ; Step size: 0.0130° 2θ; Collection time:12.75 s/step (total collection time of 2.07 min).

Nuclear Magnetic Resonance (NMR) NMR Using DRX400 Console

¹H NMR spectra were collected on a Bruker 400 MHz instrument equippedwith an auto-sampler and controlled by a DRX400 console. Samples wereprepared in DMSO-d₆ solvent, unless otherwise stated. Automatedexperiments were acquired using ICON-NMR configuration within Topspinsoftware, using standard Bruker-loaded experiments (¹CH). Off-lineanalysis was performed using ACD Spectrus Processor.

NMR Using Avance NEO Nanobay Console

¹H NMR spectra were collected on a Bruker 400 MHz instrument equippedwith an auto-sampler and controlled by a Avance NEO nanobay console.Samples were prepared in DMSO-d₆ solvent, unless otherwise stated.Automated experiments were acquired using ICON-NMR configuration withinTopspin 4.1.1 software, using standard Bruker-loaded experiments (¹H).Off-line analysis was performed using ACD Spectrus Processor 2016.

Differential Scanning calorimetry (DSC)

TA Instruments Q2000

DSC data were collected on a TA Instruments Q2000 equipped with a 50position auto-sampler. Typically, 0.5-3 mg of each sample, in apin-holed aluminium pan, was heated at 10° C./min from 25° C. to max245° C. A purge of dry nitrogen at 50 ml/min was maintained over thesample. Modulated temperature DSC was carried out using an underlyingheating rate of 2° C./min and temperature modulation parameters of±0.636° C. (amplitude) every 60 seconds (period). The instrument controlsoftware was Advantage for Q Series and Thermal Advantage and the datawere analysed using Universal Analysis or TRIOS.

TA Instruments Discovery DSC

DSC data were collected on a TA Instruments Discovery DSC equipped witha 50 position auto-sampler. Typically, 0.5-3 mg of each sample, in apin-holed aluminium pan, was heated at 10° C./min from 25° C. to 200° C.A purge of dry nitrogen at 50 ml/min was maintained over the sample. Theinstrument control software was TRIOS and the data were analysed usingTRIOS or Universal Analysis.

Thermo-Gravimetric Analysis (TGA) TA Instruments Q500

TGA data were collected on a TA Instruments Q500 TGA, equipped with a 16position auto-sampler. Typically, 5-10 mg of each sample was loaded ontoa pre-tared aluminium DSC pan and heated at 10° C./min from ambienttemperature to 350° C. A nitrogen purge at 60 ml/min was maintained overthe sample. The instrument control software was Advantage for Q Seriesand Thermal Advantage and the data were analysed using UniversalAnalysis or TRIOS.

TA Instruments Discovery TGA

TGA data were collected on a TA Instruments Discovery TGA, equipped witha 25 position auto-sampler. Typically, 5-10 mg of each sample was loadedonto a pre-tared aluminium DSC pan and heated at 10° C./min from ambienttemperature to 350° C. A nitrogen purge at 25 ml/min was maintained overthe sample. The instrument control software was TRIOS and the data wereanalysed using TRIOS or Universal Analysis.

Polarised Light Microscopy (PLM)

Samples were studied on a Nikon SMZ1500 polarized light microscope witha digital video camera connected to a DS Camera control unit DS-L2 forimage capture. The sample was viewed with appropriate magnification andpartially polarised light, coupled to a X. false-colour filter.

Scanning Electron Microscopy (SEM)

Data were collected on a Phenom Pro Scanning Electron Microscope. Asmall quantity of sample was mounted onto an aluminium stub usingconducting double-sided adhesive tape. A thin layer of gold was appliedusing a sputter coater (2Θ mA, 120 s).

Gravimetric Vapour Sorption (GVS)

Sorption isotherms were obtained using a SMS DVS Intrinsic moisturesorption analyser, controlled by DVS Intrinsic Control software. Thesample temperature was maintained at 25° C. by the instrument controls.The humidity was controlled by mixing streams of dry and wet nitrogen,with a total flow rate of 200 ml/min. The relative humidity was measuredby a calibrated Rotronic probe (dynamic range of 1.0-100%RH), locatednear the sample. The weight change, (mass relaxation) of the sample as afunction of %RH was constantly monitored by a microbalance(accuracy±0.005 mg).

Typically, 20-30 mg of sample was placed in a tared mesh stainless steelbasket under ambient conditions. The sample was loaded and unloaded at40%RH and 25° C. (typical room conditions). A moisture sorption isothermwas performed as outlined below (2 scans per complete cycle). Thestandard isotherm was performed at 25° C. at 10%RH intervals over a0-90%RH range. Typically, a double cycle (4 scans) was carried out. Dataanalysis was carried out within Microsoft Excel using the DVS AnalysisSuite.

TABLE 1 Method for SMS DVS Intrinsic experiments Parameter ValueAdsorption-Scan 1 40-90 Desorption, Adsorption-Scan 2 90-0, 0-40Intervals (% RH) 10 Number of Scans 4 Flow rate (ml/min) 200 Temperature(° C.) 25 Stability (° C./min) 0.2 Sorption Time (hours) 6 hour time outNumber of cycles 2

Chemical Purity Determination by HPLC

Purity analysis was performed on an Agilent HP1100/Infinity II 1260series system equipped with a diode array detector and using OpenLABsoftware. The full method details are provided below:

TABLE 2 HPLC method for chemical purity determinations Parameter ValueType of method Reverse phase with gradient elution Sample Preparation0.2 (equivalent free base) mg/ml in acetonitrile: water 1:1 Samplesonicated for ca. 1 h to ensure complete dissolution Column SupelcoAscends Express C18 2.7 μm 100 × 4.6 mm Column 25 Temperature (° C.)Injection (μl) 5 Detection: 255, 90 Wavelength, Bandwidth (nm) Flow Rate(ml/min) 2 Phase A 0.1% TFA in water Phase B 0.085% TFA in acetonitrileTimetable Time (min) % Phase A % Phase B 0 95 5 6 5 95 6.2 95 5 8 95 5

Water Determination by Karl Fischer Titration (KF)

The water content of each sample was measured on a Metrohm 874 OvenSample Processor at 150° C. with 851 Titrano Coulometer using Hy dranalCoulomat AG oven reagent and nitrogen purge. Weighed solid samples wereintroduced into a sealed sample vial. Approximately 10 mg of sample wasused per titration and duplicate determinations were made. An average ofthese results is presented unless otherwise stated. Data collection andanalysis were performed using Tiamo software.

Ion Chromatography (IC)

Data were collected on a Metrohm 930 Compact IC Flex with 858Professional autosampler and 800 Dosino dosage unit monitor, using ICMagicNet software. Accurately weighed samples were prepared as stocksolutions in a suitable solvent. Quantification was achieved bycomparison with standard solutions of known concentration of the ionbeing analysed. Analyses were performed in duplicate and an average ofthe values is given unless otherwise stated.

TABLE 3 IC method for cation chromatography Parameter Value Type ofmethod Cation exchange Column Metrosep C 4-250 (4.0 × 250 mm) ColumnTemperature (° C.) Ambient Injection (μl) Various Detection Conductivitydetector Flow Rate (ml/min) 0.9 Eluent 1.7 mM nitric acid 0.7 mMdipicolinic acid in a 5% acetone aqueous solution.

TABLE 4 IC method for anion chromatography Parameter Value Type ofmethod Anion exchange Column Metrosep A Supp 5-150 (4.0 × 150 mm) ColumnAmbient Temperature (° C.) Injection (μl) Various Detection Conductivitydetector Flow Rate (ml/min) 0.7 Eluent 3.2 mM sodium carbonate 1.0 mMsodium hydrogen carbonate in a 5% acetone aqueous solution.

Example 1—Preparation of crystalline mesylate Form 1 of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide

N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide(500 mg) was weighed into a 2Θ ml vial and 35 vols (17.5 ml) of aselected solvent EtOH/water (9:1 v/v) was added. All samples appeared assuspensions and were stirred (500 rpm) at 50° C. Methanesulfonic acid(1.1 mole equivalent, 1.395 ml) was added as a 1 M stock solution inTHF. The samples were all stirred for 1 hour at 50° C. before beingcooled to 5° C. at 0.1° C./min. The samples were left to stir overnightat 5° C. Observations were made immediately after the salt addition andagain once the solutions had cooled to 5° C.

Alternative Procedure 1

N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hexyl}pyrimidine-5-carboxamide (100 g) was weighed into a 5 L flask and 1.5L of ACN or EtOH was added. All samples appeared as suspensions and werestirred at 50° C. A 1.0 mole equivalent of methanesulfonic acid wasadded. The samples were all stirred for 1 hour at 50° C. before beingcooled to 5° C. The samples were left to stir overnight at 5° C. Theprecipitated solid was collected by filtration to afford the crystallinemesylate Form 1 of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideat 85% yield.

Example 2—Characterization of crystalline mesylate Form 1 of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide

Mesylate Form 1 was successfully scaled up and XRPD confirmed goodcrystallinity and the material was characterized, the results of whichare shown in Table 5 below.

TABLE 5 Solvent/method EtOH/water, cooling XRPD Mesylate Form 1, nochange on drying ¹H-NMR Consistent with structure, peak shifts,methanesulfonic acid (approximately 1 mole eq, mono salt, overlaps withAPI), 0.01 mol. Eq. residual EtOH detected HPLC purity 99.5% TGA Noweight loss prior to degradation at 220° C. DSC Large exothermaffiliated with decomposition (onset temp. 222.1° C., 433 J/g) IC 1 mol.Eq. mesylate 7 days at No change, Mesylate Form 1 40° C./75% RH 14 weeksat Mixture of Mesylate Form 1 and Mesylate 40° C./75% RH Form 2 (94.7%purity) 7 days at No change, Mesylate Form 1 25° C./97% RH 14 weeks atMesylate Form 1 (93.5% purity) 25° C./97% RH GVS Appeared stable by GVS,no hysteresis, and 0.35% reversible uptake from 0-90% RH: Slightlyhygroscopic. XRPD remains unchanged KF 0.1% water content form Smallcrystalline rods ca. 20-50 μm

The API acid stoichiometry was determined as 1:1 by ¹H-NMR and 0.01 moleeq. EtOH was identified. The retention of the parent structure was alsoconfirmed by NMR following salt formation. The material was isolated ingood purity at 99.5% by HPLC. The crystal habit for the mesylate saltwas defined as small crystalline rods which were ca. 20-50 μm in size.

There were no thermal events observed in the TGA thermogram until theonset of decomposition from ca. 220° C. The DSC was characterized by asingle exothermic event with an onset temperature at 222.1° C. (433 J/g)associated with the decomposition event by TGA.

Mesylate Form 1 appeared to be stable under variable humidityenvironments. The material was slightly hygroscopic by GVS with ˜0.35%reversible water uptake between 0-90% RH and the residue on recoveryshowed no change by XRPD. Mesylate Form 1 was unchanged by XRPD after 7days at 25° C./97% RH and 40° C./75% RH and no significant drop inpurity was noted.

Mesylate Form 1 is a crystalline non-solvated mesylate mono-salt that isa slightly hygroscopic and displayed stability up to 7 days under staticstability conditions (25° C.197% RH, 40° C.175% RH).

Example 2a—XRPD Characterization of crystalline mesylate Form 1 ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide

The peak table and XRPD for Mesylate Form 1 can be found below (Table 6,FIG. 1 ). The values for 2Θ are considered to have an error of ±0.3degrees.

TABLE 6 Angle (2θ°) Intensity % Angle (2θ°) Intensity % 3.7 100.0 22.515.2 7.5 31.9 22.9 14.1 13.3 1.4 23.1 8.1 14.9 57.4 23.4 11.2 15.4 2.724.0 5.2 15.7 1.4 24.2 5.6 16.1 2.7 24.6 2.3 16.7 9.4 24.8 2.8 16.8 3.825.3 8.6 17.3 13.5 25.6 1.9 17.7 1.4 26.4 2.5 18.0 2.3 26.8 4.6 18.4 4.027.2 1.3 18.7 5.7 28.3 2.4 19.5 2.3 28.6 2.5 19.7 13.0 29.5 2.5 20.3 3.930.1 17.3 21.0 4.2

Example 2b—Intrinsic dissolution rate of crystalline mesylate Form 1 ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide

Aqueous solubility was determined by suspending sufficient compound in0.5 ml deionized water to give a maximum final concentration of 40 mg/mlof the parent free-form of the compound. The suspension was equilibratedat 25° C., on a Heidolph plate shaker set to 750 rpm for 24 hours. Afterequilibration, the appearance was noted and the pH of the saturatedsolution was measured. Samples forming suspensions were centrifuged for4 min at 13,500 rpm. Samples were then filtered through a glass fiber Cfilter (particle retention 1.2 μm), before dilution with H₂O asappropriate.

Quantitation was by HPLC (see Table 2 for parameters) with reference toa standard solution of approximately 0.15 mg/ml in DMSO. Differentvolumes of the standard, diluted and undiluted sample solutions wereinjected. The solubility was calculated using the peak areas determinedby integration of the peak found at the same retention time as theprincipal peak in the standard injection. Analysis was performed on anAgilent HP1100/Infinity II 1260 series system equipped with a diodearray detector and using OpenLAB software.

TABLE 7 Parameter Value Type of method Reverse phase with gradientelution Column PhenomenexLuna, C18 (2) 5 μm 50 × 4.6 mm Column 25Temperature (° C.) Standard Injections (μl) 1, 2, 3, 4, 5, 7 TestInjections (μl) 1, 2, 3, 10, 15, 20 Detection: 260, 90 Wavelength,Bandwidth (nm) Flow Rate (ml/min) 2 Phase A 0.1% TFA in water Phase B0.085% TFA in acetonitrile Timetable Time (min) % Phase A % Phase B 0.095 5 1.0 80 20 2.3 5 95 3.3 5 95 3.5 95 5 4.4 95 5

Thermodynamic aqueous solubility of mesylate and free base forms aresignificantly different, as shown in Table 8. Free base is essentiallyinsoluble in water. The mesylate shows excellent solubility at 40 mg/mLand the final pH of saturated solution was ˜3.2.

The intrinsic dissolution rates (IDR) for the Mesylate Form 1 salt wasdetermined in Fasted State Simulated Gastric Fluid FaSSGF media andcompared with both Free Form A and Free Form B of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.The IDR were not determined in Fasted State Simulated Intestinal Fluid(FaSSIF) or Fed State Simulated Intestinal Fluid (FeSSIF) media after alow absorbance values were noted for the parent free form compound thatdid not allow for complete data analysis. The Mesylate Form 1 saltexhibited a high IDR with an intrinsic dissolution rate of 9.1mg/min/cm²(ca 8 times of free base form A) and the majority of the discdisintegrated in this media.

TABLE 8 Solubility and intrinsic dissolution rates in water or FaSSGFfor salt forms and free form polymorphs Solubility in water mg/mL IDR(mg/min/cm²) in Form (pH of saturated solution) FaSSGF Free Base 0.0011.1 Form A (pH = 7.4) Free Base 0.001 1.8 Form B (pH = 7.4) Mesylate 409.1 Form 1 (pH = 3.2)

FIG. 1 shows the X-ray powder diffractogram of crystalline mesylate Form1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

FIG. 2 shows the ¹H NMR spectra of crystalline mesylate Form 1 salt ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

FIG. 3 shows the thermal gravimetric analysis pattern of crystallinemesylate Form 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

FIG. 4 shows the HPLC analysis of crystalline mesylate Form 1 salt ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

FIG. 5 shows the microscope image of crystalline mesylate Form 1 salt ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

FIG. 6 shows the GVS kinetic plot of crystalline mesylate Form 1 salt ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

FIG. 7 shows the GVS isotherm plot of crystalline mesylate Form 1 saltof N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1 . 0]hex-3-yl}pyyrimidine-5-carboxamide.

FIG. 8 shows the X-ray powder diffractogram of crystalline mesylate Form1 salt after GVS analysis of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

FIG. 9 shows the X-ray powder diffractogram of crystalline mesylate Form1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamideafter storage under the indicated conditions.

FIG. 10 shows the HPLC analysis of crystalline mesylate Form 1 salt ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide after storage under the indicated conditions.

Example 3—Characterization of amorphous mesylate of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide

Crystalline mesylate Form 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide(10 mg) was weighed into 4 HPLC vials. The relevant solvent (200₁1.1, 20volumes) was added and the samples mixed on a vortex mixer to aiddissolution, observations were then made. If a clear, transparentsolution was obtained, the solution was filtered using a 0.45₁.tm PTFEmembrane Acrodisc filter to remove any remaining solid particles. Thesolutions were then flash-frozen in an acetone/dry ice bath, and placedon the freeze dryer overnight. The next day, samples were removed fromthe freeze dryer, and analyzed by XRPD to confirm the amorphous solidstate. The sample was further analyzed by mDSC and ¹H NMR to determineresidual solvent content and identify the glass transition of theamorphous solid. The results can be found in Table 9. The NMR identified0.07 mol. eq. residual THF and the modulated DSC identified a high glasstransition temperature, Tg=126.7° C. The purity was not significantlyimpacted by the lyophilization process and the amorphous showed moderatestability up to 7 days at 25° C./97% RH and 40° C./75% RH with appearinglargely amorphous with a small reflection appearing at 3.7° 2θ.

TABLE 9 Characterization of amorphous mesylate salt by lyophilizationfrom THF/H₂O (1:1) XRPD Amorphous ¹H-NMR Residual THF (0.07 mol. eq.)mDSC* T_(g): 126.7° C. HPLC Purity 97.7% Static 40° C./ Amorphous, withlow- storage 75% RH level peak at 3.7° 2θ 1 week 25° C./ Amorphous, withlow- 97% RH level peak at 3.7° 2θ

FIG. 11 shows the X-ray powder diffractogram of the amorphous mesylatesalt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

FIG. 12 shows the TGA and DSC pattern of the amorphous mesylate salt ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyyrimidine-5-carboxamide.

Example 4—Characterization of crystalline mesylate Form 2 of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide

Mesylate Form 1 (400 mg) was placed in a 100 ml round-bottomed flask. Toit was added THF/water (9:1 v/v) (28 ml, 70 volumes) and the sample wasstirred at 50° C. The sample was partially soluble, and the temperatureincreased to 60° C. A white precipitate was observed, the amount ofwhich seemed to increase with increased temperature/further dissolutionof the initial solid. An aliquot was taken of the suspension, placed ona flat XRPD holder, and allowed to dry, to leave behind a thin residue.This was then analyzed by XRPD and found to be amorphous.

The sample was then heated to 70° C., where the solution remainedturbid. The suspension was cooled again to 60° C., where an additional 1ml was added, followed by further 1 ml aliquots added until anadditional 9 ml had been added (total solvent: 38 ml, 95 volumes). Thesolution remained turbid and the temperature was again increased to 70°C., where a clear, colorless solution was obtained. The solution wascooled to 5° C. at 0.1° C./minute with stirring overnight.

The next morning, a thin suspension was observed. A small aliquot wastaken and allowed to dry on a flat XRPD holder. The sample was observedto dry to a glass-like appearance, the solid was collected and flattenedfor analysis by XRPD. The sample appeared amorphous, with low-levelcrystalline peaks. The sample was stirred at 5° C. for a further twodays, after which another aliquot was taken, and allowed to dry on aflat XRPD holder. The sample was isolated on a Buchner funnel withdrying for ˜5 minutes to afford Mesylate Form 2.

TABLE 10 Characterization of Mesylate Form 2 Solvent 10% H₂O/THF XRPDMesylate Form 2 ¹H-NMR Consistent with structure. Mesylate present (~0.9mol. eq.-overlapping peaks with API CH₂). Residual THF (0.008 mol. eq.,0.1% w/w) HPLC Purity 99.5% DSC Broad endotherm, onset 124.7° C. (240J/g), two small exotherms with onset at 155.4° C. (2 J/g) and 171.4° C.(2 J/g) TGA 3.7% mass loss ambient-170° C. furthermass loss > 170° C.40° C./75% RH Mesylate Form 2, 99.5% purity 25° C./97% RH Mesylate Form2, 99.5% purity KF 3.6% water (1 mol. eq.) IC 17.7% mesylate (0.9 mol.eq.) GVS ~0.4% reversible water uptake between 0-90% RH XRPD Post-GVS:Mesylate Form 2 SEM Large agglomerates (<200 μm in size) comprised ofirregular-shaped primary particles (≤10 μm in size) PLM Largeagglomerates observed (~200 μm in size), smaller particles/agglomeratesobserved (~100 μm). Smaller, individual particles too small to beobserved. Assignment Monohydrate

The ¹-H NMR was consistent with the structure, containing ˜0.9 mol. eq.mesylate, and there was low residual THF (0.008 mol. eq.). The ICanalysis confirmed 0.9 mol. eq. Mesylate to be present. There was a 3.7%mass loss ambient—170° C. by TGA which was confirmed as water where KFidentified 3.6% water (equating to 1 mol. Eq. water). The DSC thermogramshowed a broad endotherm with onset at 124.7° C., which overlapped withthe water loss, and was followed by two small exotherms with onsets at155.4° C. and 171.4° C. From GVS analysis, Mesylate Form 2 was slightlyhygroscopic, with ˜0.4% reversible water uptake between 0-90% RH and thehydrate appears to be relatively stable as the 1 mol. eq. of bound waterwas not lost during the desorption cycles. This was supported by theXRPD post-GVS being unchanged as Mesylate Form 2 to remain. Afterstorage at 25° C./97% RH and 40° C./75% RH) for 1 week the form wasunchanged by XRPD with no significant drop in HPLC purity noted.Analysis of particle size and morphology by microscopy showed thepresence of agglomerates of ˜200 μm in size, comprised of primaryirregular-shaped particles (≤10 μm) in size. HPLC showed a purity of99.5%. In summary Mesylate Form 2 is a crystalline monohydratemono-mesylate salt that is slightly hygroscopic.

Example 4a—XRPD Characterization of crystalline mesylate Form 2 ofN-hydroxy 2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide

The peak table for Mesylate Form 2 and XRPD for the sample can be foundbelow (Table 11, FIG. 14 ). The values for 2Θ are considered to have anerror of ±0.3 degrees.

TABLE 11 XRPD peak table for Mesylate Form 2 Angle (°2θ) Intensity %Angle (°2θ) Intensity % 7.3 27.5 25.0 19.9 12.4 6.2 26.3 29.4 14.6 100.026.9 83.1 14.8 51.3 27.7 28.6 15.6 13.1 28.4 26.1 16.4 47.4 28.6 17.817.4 38.1 29.4 22.8 18.4 53.2 29.7 13.8 19.2 19.1 31.0 9.9 19.5 57.931.5 4.9 20.5 39.7 32.9 12.4 20.7 28.5 33.1 7.9 21.2 20.2 34.6 21.6 21.944.1 35.4 21.4 22.2 23.2 36.9 27.2 22.5 4.9 38.5 8.5 23.5 38.3 39.0 5.723.8 9.7 39.7 6.6 24.1 22.0 41.2 6.9 24.3 98.8 41.8 24.6

FIG. 13 shows the XRPD of crystalline mesylate Form 2 of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine

FIG. 14 shows the TGA and DSC of crystalline mesylate Form 2 ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidinecarboxamide.

FIG. 15 shows the GVS kinetic plot of crystalline mesylate Form 2 ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

FIG. 16 shows the GVS isotherm plot of crystalline mesylate Form 2 ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

Example 5—Characterization of crystalline mesylate Form 3 of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide

Mesylate Form 1 was dissolved in H₂O (15 ml, ˜2Θ volumes) in a 2Θ mlscintillation vial at 50° C. to produce a clear, transparent solution.Undissolved particulates were observed (possible fibers from filterpaper), and so the solution was filtered through an acrodisc filter(0.45 μm pore size). The sample was cooled to 5° C. at 0.1° C./minuteand stirred at 5° C. overnight. The next day, the sample was observed tobe a clear, transparent yellow solution, which turned turbid throughoutthe day. The next day, a peachy-colored thick suspension was observed. Asmall aliquot of the suspension was taken and analyzed by XRPD. Thesample was isolated over gentle vacuum to remove excess water. The wetfilter cake was air dried only. A small amount of the damp solid wasthen taken, which dried slightly on the holder prior to analysis by XRPD(indicated by color change from darker to lighter). The XRPD holdercontaining the aliquot taken from the suspension was re-analyzed afterdrying in air for ˜2 hours.

Analysis of the aliquot taken from the suspension after being left tostir overnight showed it to be Mesylate Form 3, however, after leavingit to dry for ˜2 hour on the XRPD holder it was shown to have becomepoorly crystalline. This behavior suggested that Mesylate Form 3 waslikely to be a metastable hydrate. Identifying that excessive dryingreduced the crystallinity resulted in the gentle isolation and air dyingonly of the bulk sample which successfully provided crystalline MesylateForm 3 as summarized in Table 12.

TABLE 12 Characterization of Mesylate Form 3 Solvent Water XRPD MesylateForm 3 ¹H-NMR Consistent with structure 1 mol. eq. mesylate present(overlapping peaks with API CH₂) HPLC Purity 96.5% DSC Complexthermogram with an endotherm with onset at 48.2° C. (62 J/g), followedby additional event behavior up to a sharp endotherm, onset: 113.0° C.(59 J/g). TGA 28.8% mass loss from ambientto 135° C. Additional massloss observed > 205° C. 40° C./75% RH Mesylate Form 5, 97.0% purity 25°C./97% RH Mesylate Form 3, 96.6% purity KF 46.6% water (19.1 mol. eq.)*IC 13.2% mesylate (0.9 mol. eq.) assuming 9 water molecules GVS Sorption1 cycle: starting at 25.1% water content at 40% RH and has 2% wateruptake up to 90% RH Desorption Cycle 1 22% water loss from 30-20% RHSorption/desorption cycle 2~12% water uptake from 0-90% RH withhysteresis between 0-60% RH. XRPD Post-GVS: Poorly crystalline broadreflections may match Mesylate Form 1 SEM Agglomerates (>200 μm)comprised of microcrystalline particles (laths, <1-6 μm in size-longestlength, primary particle size). PLM Large agglomerates observed (~200μm) consisting of smaller particles also observed (<10 μm) AssignmentMetastable nonahydrate

Mesylate Form 3 was isolated in good crystallinity and there was a dropin purity to 96.5%. The ¹H NMR remained consistent with the structureand 1 mol. eq. mesylate identified present. IC analysis confirmed thereto be 0.9 Mol. eq. mesylate (assuming 9 water molecules in the masscalculation. The TGA thermogram had a 28.8% mass loss ambient to 135° C.This was suspected to be bound water and potentially some residualsurface water from the gentle sample drying. The Karl Fisher confirmedwater was present with 46.6% water content. It is plausible thedifference with respect to the TGA was due to the time differencebetween the analyses which could have resulted in the sample drying to amore stable level of water content. The DSC thermogram was complexdisplaying a broad endotherm with onset at 48.2° C. followed by amodulating baseline that was likely due to other thermal behavior. Thiswas followed by sharp endotherm with an onset at 113.0° C.

The GVS analysis was critical in determining the nature of Mesylate Form3. At the start of the GVS experiment at 40% RH the kinetic plot shows aloss of water mass until it stabilizes at 25.1% water content. Ninewater molecules were calculated to be 23.5% w/w. the first sorptioncycle from 40% -90% RH shows that 2% water uptake from the atmosphereoccurs. The desorption cycle then loses incremental water down to 30% RH(to 24.3% water, close to ideal 9 mol. eq. water). The further drop inhumidity to 20% RH is where the majority of this water is then lostwhich then further drops to down to 0% RH. The second sorption profileis different with ˜12% water uptake observed between 0-90% RH which islost on the desorption cycle. The final sorption cycle up to 40% RHlooks similar to sorption cycle 2 and suggests a hysteresis between0-60% RH. The XRPD post-GVS was poorly crystalline with broadreflections that didn't match well with any of the known hydrates andhas some reflection in common which may match Mesylate Form 1. From thecombination of TGA, KF and GVS data Mesylate Form 3 is assigned as anonahydrate (nine water molecules).

Mesylate Form 3 remained unchanged by XRPD when placed under staticstorage for 1 week at 25° C./97% RH showed conversion to Mesylate Form 5at 40° C./75% RH again indicating some metastability to the form.

In summary, Mesylate Form 3 is assigned as a metastable nonahydrate ofthe mono-mesylate salt. The metastable nature of the form has beendisplayed through the drying processes on isolation, the differentsorption profiles observed between the first and second cycle of the GVS(and post-GVS XRPD) and its conversion to the sesquihydrate MesylateForm 5 after storage at 40° C./75% RH.

Example 5a—XRPD Characterization of crystalline mesylate Form 3 ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide

The peak table and XRPD for Mesylate Form 3 can be found below (Table12, FIG. 17 ). The values for 2Θ are considered to have an error of ±0.3degrees.

TABLE 12 XRPD peak table for Mesylate Form 3 Angle (°2θ) Intensity %Angle (°2θ) Intensity % 6.3 24.3 23.8 6.5 8.4 9.5 24.2 8.3 9.5 100.024.8 27.0 10.3 50.4 25.4 9.6 13.0 1.9 25.8 10.4 13.4 2.7 26.2 12.4 14.828.6 26.7 10.3 15.4 3.4 27.2 16.6 15.8 10.1 27.5 12.4 16.5 19.7 27.9 5.616.8 14.6 28.3 5.7 17.4 2.8 28.6 7.5 18.7 11.5 29.4 8.4 19.0 15.9 29.87.6 19.4 49.2 30.5 9.3 20.7 11.9 31.3 9.2 21.3 8.3 31.8 14.8 21.6 11.832.5 8.6 22.5 12.3 32.8 9.2 22.8 7.0 33.3 13.4 23.3 24.3

FIG. 17 shows the XRPD of crystalline mesylate Form 3 of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

FIG. 18 shows the TGA and DSC of crystalline mesylate Form 3 ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyyrimidine-5-carboxamide.

FIG. 19 shows the GVS kinetic plot of crystalline mesylate Form 3 ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyyrimidine

FIG. 20 shows the GVS isotherm plot of crystalline mesylate Form 3 ofN-hydroxy 2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex -3-yl}pyyrimidinecarboxamide.

Example 6—Characterization of crystalline mesylate Form 4 of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide

The amorphous mesylate salt was generated using lyophilization asdescribed in Example 3. The amorphous solid (750 mg) was suspended inTHF/water (9:1 v/v) (15 ml, 2Θ volumes) and stirred at 5° C. producing awhite suspension. The suspension was stirred overnight at 5° C. and thenext morning, an aliquot was taken, placed on a flat XRPD holder andanalyzed by XRPD. The suspension was then isolated over a Buchner funneland dried for ˜15 minutes under vacuum. The solid was re-analyzed byXRPD post-isolation and drying.

TABLE 13 Characterization of Mesylate Form 4 Solvent 10% H₂O/THF XRPDCrystalline-Mesylate Form 4 ¹H-NMR Consistent with structure, (0.9 mol.eq. mesylate). THF signal not observed HPLC purity 99.3% DSC Overlappingendothermic event with onset 51.0° C. (269 J/g) No further eventsobserved. TGA 9.6% mass loss ambient-92° C. Furthermass loss above 200°C. 40° C./75% RH Mixture Mesylate Form 4 and Mesylate Form 1, 99.4%purity 25° C./97% RH Mesylate Form 1, 99.5% purity KF 12.6% water (3.2mol. eq.)* IC 17% mesylate (1.0 mol. eq.) GVS Different behaviordisplayed on cycle 1 and cycle 2 Cycle 1: 9.4% starting water content,0.7% water uptake from 40-90% RH, significant step loss from 20 to 10%RH on desorption Cycle 2: 3.6% water uptake between 0-90% RH displayinghysteresis loop Post-GVS: Converted to Mesylate Form 1 by XRPD SEM Largeagglomerates observed~600 μm in size, comprised of smaller lath-typeparticles~30 μm in size. Particles > 5 μm present. PLM Largeagglomerates observed~600 μm in size, smaller particles present~10 μm insize Assignment Metastable trihydrate

The sample was isolated in good crystallinity with high purity at 99.3%by HPLC. The ¹H NMR confirmed there to be at least 0.9 mol. eq. mesylateand the ¹H-NMR spectrum was consistent with the structure. The TGA had amass loss of 9.6% ambient to 92° C. which was suspected to be water dieto the absence of residual THF. KF analysis showed 12.6% water (equatingto ˜4 mol. eq. water). The DSC displayed overlapping endothermic eventswith an onset at 51.0° C. and overlapped with the water loss event byTGA.

The GVS analysis showed different behaviors between cycle 1 and cycle 2.The starting water content at 40% RH was 9.4% water with an additional0.7% water uptake in the first sorption cycle (40-90% RH). During thedesorption cycle there was gradual water loss (0.8% water) down to 20%RH with a significant loss (-9% water content) between 2Θ to 10% RH.During the second cycle, a total water uptake of 3.6% is observedbetween 0-90% RH, with hysteresis observed between thesorption/desorption steps. The GVS data was in closer agreement to theTGA loss than the KF and the assessment was made that Mesylate Form 4contained 3 mol. eq. water. The discrepancy with the KF may have beendue to differences in sampling time when the sample may have hadadditional residual water from the initial isolation. The XRPD post-GVSshowed conversion to Mesylate Form 1.

Mesylate Form 4 was unchanged by XRPD after static storage at 40° C./75%RH for 1 week with good purity of 99.4%. By contrast conversion toMesylate Form 1 after storage at 25° C./97% RH was observed and retaineda good purity of 99.5%. The microscopy analysis showed the presence oflarge agglomerates ˜600 μm in size, comprised of smaller lath-typeparticles ˜30 μm in size. Finer particles of 5-10 μm in size were alsoobserved.

In summary, Mesylate Form 4 is a metastable trihydrate of themono-mesylate salt as supported by the GVS and TGA analysis. Evidence oflimited stability were displayed by conversion to Mesylate Form 1 postGVS analysis and after storage at 25° C./97% RH.

Example 6a—XRPD Characterization of crystalline mesylate Form 4 ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidinecarboxamide

The peak table and XRPD for Mesylate Form 4 can be found below (Table14, FIG. 21 ). The values for 2Θ are considered to have an error of ±0.3degrees.

TABLE 14 XRPD peak table for Mesylate Form 4 Angle (°2θ) Intensity % 3.5100.0 6.9 10.8 10.3 55.7 13.8 10.2 15.2 15.2 16.5 6.8 17.2 39.8 17.736.5 18.8 5.4 19.1 8.9 20.6 10.9 21.9 9.3 22.4 25.5 23.0 7.2 23.5 17.824.2 10.7 24.7 25.7 25.1 9.0 25.5 10.1 26.4 23.7 27.4 9.0 28.0 7.0 28.95.9

FIG. 21 shows the XRPD of crystalline mesylate Form 4 of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

l FIG. 22 shows the TGA and DSC of crystalline mesylate Form 4 ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidinecarboxamide.

FIG. 23 shows the GVS kinetic plot of crystalline mesylate Form 4 ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

FIG. 24 shows the GVS isotherm plot of crystalline mesylate Form 4 ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

Example 7—Characterization of crystalline mesylate Form 5 of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide

Mesylate Form 5 was obtained during an attempted preparation of MesylateForm 2, from a solution in THF/water (9:1 v/v). Mesylate Form 5 was alsoobserved when Mesylate Form 3 was held at 40° C./75% RH for 1 week. Thecharacterization of mesylate Form 5 is shown below.

TABLE 15 Characterization of Mesylate Form 5 Solvent 10% H₂O/THF XRPDMesylate Form 5 ¹H-NMR Consistent with structure Mesylate present (~0.9mol. eq. overlapping peaks with API CH₂) No THF signal detected HPLCPurity 99.4% DSC Small endotherm onset 28.4° C. (6 J/g), broad endothermonset 56.8° C. (52 J/g) Endotherm, onset 152.3° C. (6 J/g) followed byexotherm, onset 163.3° C. (14 J/g) TGA 5.9% mass loss ambient-130° C.further mass loss > 195° C. 40° C./75% RH Unchanged: Mesylate Form 5,99.5% purity 25° C./97% RH Unchanged: Mesylate Form 5, 99.5% purity KF5.6 % water (1.6 mol. eq.) IC* 21.8% mesylate (1.1 mol. eq) GVS 4.7%reversible water uptake from 0-90% RH. Hysteresis observed 60-30% RHXRPD Post-GVS: Mesylate Form 5 SEM Agglomerates comprised of irregularparticles and laths (~100 μm in size). Primary particle size ≤ 10 μm PLMLarge agglomerates present (~300 μm). Smaller particles not easily seenAssignment Sesquihydrate

The ¹H NMR was consistent with the structure with ˜0.9 mol. eq. mesylatepresent and no residual THF signal was detected. The sample wasrecovered in good purity at 99.4% by HPLC. The TGA thermogram had atwo-step mass loss of 5.9% which was suspected to be water. Karl Fisheranalysis confirmed there to be 5.6% water content (equating to 1.6 mo.eq. water). The DSC had a small endotherm with an onset at 28.4° C.followed by a broad endotherm with onset at 56.8° C. These twoendotherms overlapped well with the two-step mass loss. These werefollowed by an endotherm with onset at 152.3° C. and a subsequentexotherm with onset at 163.3° C. The GVS analysis indicated MesylateForm 5 to be hygroscopic with 4.7% reversible water uptake from 0-90%RH. From the GVS isotherm and kinetic plots it appears that the form isquite stable with no indication the bound water was lost. This wascorroborated with the XRPD post-GVS analysis which was unchanged asMesylate Form 5. The microscopy analysis shows the presence ofagglomerates ˜100 μm in size, comprised of irregular particles andlaths, with a primary particle size ≤10 μm. When placed under staticstorage conditions for 1 week, Mesylate Form 5 was unchanged by XRPD atboth 25° C./97% RH and 40° C./75% RH.

In summary, Mesylate Form 5 has been identified as a stablesesquihydrate (q.5 mol. eq. water) of the mono-mesylate salt that ishygroscopic, as determined by GVS. The form showed short-term solid formstability, remaining unchanged by XRPD after GVS and static storage atelevated conditions up to 1 week.

Example 7a—XRPD Characterization of crystalline mesylate Form 5 ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide

The peak table and XRPD for Mesylate Form 5 can be found below (Table16, FIG. 25 ). The values for 2Θ are considered to have an error of ±0.3degrees.

TABLE 16 XRPD peak table for Mesylate Form 5 Angle (°2θ) Intensity %Angle (°2θ) Intensity % 7.8 7.0 26.4 16.2 11.5 3.3 26.9 25.4 11.7 4.627.4 44.0 12.0 21.7 28.1 16.4 14.1 12.7 28.6 8.5 14.6 12.0 29.0 11.215.7 63.7 29.9 12.4 16.1 7.5 30.5 9.1 16.8 83.7 30.9 24.1 17.5 5.6 31.77.9 18.0 72.1 32.0 6.0 19.2 5.4 32.5 8.9 20.2 16.5 32.9 10.7 20.4 19.933.1 7.9 20.7 100.0 33.9 30.1 21.1 33.2 34.2 27.4 21.5 33.8 34.6 36.822.5 31.8 35.2 12.4 23.2 21.8 35.6 12.4 23.6 22.3 36.7 30.0 24.0 9.138.1 10.6 24.3 31.8 39.0 10.1 24.9 19.3 39.3 8.4 25.2 21.2 40.3 10.725.5 11.5 40.9 22.1

FIG. 25 shows the XRPD of crystalline mesylate Form 5 of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

FIG. 26 shows the TGA and DSC of crystalline mesylate Form 5 ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyyrimidine

FIG. 27 shows the GVS kinetic plot of crystalline mesylate Form 5 ofN-hydroxy 2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex -3-yl}pyyrimidine carboxamide.

FIG. 28 shows the GVS isotherm plot of crystalline mesylate Form 5 ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyyrimidine-5-carboxamide.

Example 8—Characterization of crystalline mesylate Form 6 of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide

Mesylate Form 6 was obtained from cooling a turbid solution in DMF to 5°C. The characterization data is summarized in Table 17. The ¹-H NMRshowed 0.7 mol. eq. DMF ˜0.8 mol. eq. mesylate present in the solid. TheTGA had 9.0% mass loss that matched the DMF content by NMR. A smallendotherm was observed with onset at 51.1° C. by DSC, followed by abroad endotherm at 84.7° C., which corresponded to the mass lossobserved by TGA. An additional, smaller endotherm was observed at 124.7°C. The form converted to Mesylate Form 1 after 1 week at both 40° C./75%RH and 25° C./97% RH. Mesylate Form 6 was tentatively assigned as aD1VIF solvate that can desolvate under certain conditions.

TABLE 17 Characterization of Mesylate Form 6 Solvent DMF XRPDCrystalline, mesylate Form 6 ¹H-NMR Consistent with proposed structure,shifted peaks. 0.7 mol. eq. DMF, 1.5 mol. eq mesylate DSC Smallendothermic event, onset 51.1° C. (0.2 J/g), broad endotherm onset 84.7°C. (79.8 J/g), corresponding with mass loss. Small endotherm onset124.7° C. (0.7 J/g) TGA 9.0% mass loss~78-113° C., additional mass lossobserved > 215° C. 40° C./75% RH Mesylate Form 1 25° C./97% RH MesylateForm 1 Tentative DMF solvate assignment

Example 8a—XRPD Characterization of crystalline mesylate Form 6 ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide

The peak table for Mesylate Form 6 and XRPD for the sample can be foundbelow (Table 18, FIG. 29 ). The values for 2Θ are considered to have anerror of ±0.3 degrees.

TABLE 18 XRPD peak table for Mesylate Form 6 Angle (°2θ) Intensity %Angle (°2θ) Intensity % 4.3 22.4 20.3 18.1 6.7 35.3 20.7 32.8 8.7 19.721.3 15.8 10.4 19.7 21.7 12.4 12.5 14.9 22.4 13.3 12.9 14.6 22.9 100.013.6 18.9 23.5 21.0 14.0 16.3 25.2 19.2 15.7 26.6 25.4 22.6 16.2 43.725.7 21.0 17.2 25.1 25.9 27.6 18.9 18.8 27.4 20.8 19.5 14.4 27.8 15.420.1 12.9

FIG. 29 shows the X-ray powder diffractogram of crystalline mesylateForm 6 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

FIG. 30 shows the TGA and DSC pattern of crystalline mesylate Form 6salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

Example 9—Characterization of crystalline mesylate Form 7 of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide

Mesylate Form 7 was obtained from cooling a solution in NMP to 5° C. Thecharacterization of Mesylate Form 7 is shown in Table 19. ¹H NMRanalysis showed 1 mol. eq. NMP and a lower 0.7 mol. eq. mesylatepresent. Due to insufficient sample remaining, thermal analysis was notpossible. Mesylate Form 7 converted to Mesylate Form 1 after 1 weekstorage at 40° C./75% RH and 25° C./97% RH. Mesylate Form 7 wastentatively assigned as an NMP solvate.

TABLE 19 Characterization of Mesylate Form 7 Solvent NMP XRPDCrystalline, mesylate Form 7 ¹H-NMR 1 mol. eq. NMP, 0.7 mol. eq.mesylate DSC Insufficient sample for analysis TGA Insufficient samplefor analysis 40° C./75% RH Mesylate Form 1 25° C./97% RH Mesylate Form 1Tentative assignment NMP solvate

Example 9a—XRPD Characterization of crystalline mesylate Form 7 ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide

The peak table for Mesylate Form 7 and XRPD for the sample can be foundbelow (Table 20, FIG. 31 ). The values for 2Θ are considered to have anerror of ±0.3 degrees.

TABLE 20 XRPD peak table for Mesylate Form 7 Angle (°2θ) Intensity %Angle (°2θ) Intensity % 4.2 9.7 20.2 22.5 6.7 27.6 20.6 56.6 8.4 15.121.0 13.6 10.4 22.2 21.4 31.8 12.5 16.0 21.8 9.8 13.7 13.6 22.3 13.315.6 50.3 22.9 91.9 16.3 100.0 23.3 29.2 16.7 16.8 23.9 12.0 16.9 14.924.5 11.7 17.6 11.1 25.2 20.6 17.8 9.2 25.6 15.2 18.4 10.0 26.1 14.218.9 11.0 26.6 18.7 19.5 11.6 27.7 25.7

FIG. 31 shows the X-ray powder diffractogram of crystalline mesylateForm 7 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

Example 10—Characterization of crystalline mesylate Form 8 of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidinecarboxamide

Mesylate Form 8 was obtained following maturation temperature cycling(RT/50° C.) of the amorphous salt in DMF. The characterization resultsare shown in Table 21. The ¹-H NMR analysis showed approximately 0.9mol. eq. DMF ad ˜0.9 mol. eq. mesylate. The TGA had a 12.2% mass loss98-134° C. that was in close agreement with the DMF content. The DSCshowed an overlapping broad and a sharp endotherm, the latter with onsetat 98.8° C. After static storage of the form converted to Mesylate Form1 after 1 week at 40° C./75% RH and 25° C./97% RH. Mesylate Form 8 wastentatively assigned as another DMF solvate.

TABLE 21 Characterization of Mesylate Form 8 Solvent DMF XRPDCrystalline, Mesylate Form 8 ¹H-NMR ~0.9 mol. eq. DMF, ~0.9 mol. eq.mesylate DSC Broad endothermic event overlapping with very sharpendotherm, onset 98.8° C. (108 J/g) TGA 12.2% mass loss 98-134° C. (0.75mol. eq. DMF) 40° C./75% RH Mesylate Form 1 25° C./97% RH Mesylate Form1 Tentative DMF solvate assignment

Example 10a—XRPD Characterization of crystalline mesylate Form 8 ofN-hydroxy 2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide

The peak table for Mesylate Form 8 and XRPD for the sample can be foundbelow (Table 22, FIG. 32 ). The values for 2Θ are considered to have anerror of ±0.3 degrees.

TABLE 22 XRPD peak table for Mesylate Form 8 Angle (°2θ) Intensity %Angle (°2θ) Intensity % 4.4 100.0 18.2 23.1 6.8 61.4 19.0 11.7 8.7 51.220.4 24.0 10.2 16.0 20.8 19.9 10.4 13.1 21.4 17.7 13.1 19.2 21.8 7.513.6 9.0 22.5 14.8 14.1 43.4 23.0 12.4 15.7 9.0 26.3 14.4 16.2 57.0 26.813.3 17.3 18.0 27.5 12.7

FIG. 32 shows the X-ray powder diffractogram of crystalline mesylateForm 8 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

FIG. 33 shows the TGA and DSC pattern of crystalline mesylate Form 8salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

Example 11—Characterization of crystalline mesylate Form 9 of N-hydroxy2-{6-[(6-fluoro-quinolin-32-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide

Mesylate Form 1 was dissolved in DMSO/acetone (1:1 v/v) (35 ml, 35volumes) at 50° C. with stirring to produce a clear, yellow solution.The sample was stirred for 1 hour further at 50° C. before cooling to 5°C. at 0.5° C./minute and was stirred at 5° C. overnight. The resultingwhite suspension was filtered over a Buchner funnel and dried for ca. 15minutes. A small sample was taken and analyzed by XRPD. The solid wasisolated in 57% yield, and was further characterized by ¹H-NMR, TGA, DSCand KF and stored under elevated static conditions.

XRPD confirmed the isolation of Mesylate Form 9. The ¹H NMR showed thesample to contain 2.9 mol. eq. DMSO, with residual acetone also present(<0.01 mol. eq.). The TGA thermogram showed a large mass loss, of 41.2%,corresponding to 4.3 mol. eq. DMSO. Karl Fisher indicated there was 4.8%water content. The higher DMSO content in this sample in addition towater content may be due to insufficient drying of the sample at scale.The DSC thermogram had a broad endotherm at 78.2° C. (which may havepossible overlapping events), overlapped with the mass loss observed byTGA. Mesylate Form 9 converted under storage at both 40° C./75% RH and25° C./97% RH to Mesylate Form 1, with the sample stored at 40° C./75%RH showing a color change to yellow. The analysis indicated to MesylateForm 9 being a DMSO solvate and with a more appropriate drying protocol,the DMSO content is likely lower similar to the screening sample.

TABLE 23 Characterization of Mesylate Form 9 Solvent DMSO/Acetone 1:1XRPD Crystalline, matches Mesylate Form 9 ¹H-NMR 2.9 mol. eq. DMSO;residual Acetone (<0.01 mol. eq.), sample likely remains wet due toinsufficient drying Thermal TGA 41.2% mass loss observed ambient-247° C.Analysis (4.3 mol. eq. DMSO), continued mass loss up to 350° C.Additional; mass loss likely due to insufficient drying. DSC Broadendotherm observed at 78.2° C., (poss. overlapping events, 57.1 J/g),corresponding to mass loss. Additional events > 173° C., likelycorresponding to degradation. KF 4.8% water present (1.4 mol. eq.) Colorchange of solid observed from white to light brown Static 40° C./ Sampleappeared ‘damp’-yellow solid present Storage/ 75% RH Mesylate Form 1 1week 25° C./ Sample appeared wet-white solid still present 97% RH Poorlycrystalline-Mesylate Form 1

Example 11a—XRPD Characterization of crystalline mesylate Form 9 ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide

The peak table for Mesylate Form 9 and XRPD for the sample can be foundbelow (Table 24, FIG. 34 ). The values for 2Θ are considered to have anerror of ±0.3 degrees.

TABLE 24 XRPD peak table for Mesylate Form 9 Angle (°2θ) Intensity %Angle (°2θ) Intensity % 4.2 52.5 22.7 5.7 8.4 42.6 23.1 6.4 8.6 22.823.6 11.5 11.3 7.7 23.8 9.6 14.7 14.7 24.1 18.7 15.0 25.4 24.8 6.3 16.913.0 25.6 4.5 17.2 100.0 25.9 6.5 18.5 13.5 26.1 4.3 19.7 5.6 26.3 4.519.9 5.9 26.7 2.7 20.9 9.3 28.0 4.6 22.2 18.1 28.3 6.1 22.5 9.1

FIG. 34 shows the X-ray powder diffractogram of crystalline mesylateForm 9 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

FIG. 35 shows the TGA and DSC pattern of crystalline mesylate Form 9salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicydo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.

Example 12—Comparative studies between crystalline mesylate forms ofN-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide

The polymorph studies of the mesylate salts of compound 1 yielded 10forms: an amorphous form, an anhydrate (Form 1) 4 hydrates (Forms 2-5),2 DMF solvates (Forms 6 and 8), an NMP solvate (Form 7), and a DMSOsolvate (Form 9). The solvates were unstable, converting to Form 1 at25° C./97% RH and 40° C./75% RH.

Form 2 was characterizes as a monohydrate, a slightly hygroscopic formthat was stable after 1 week at elevated conditions. A metastablenonahydrate (Form 3) was identified and was unstable to drying (losingsignificant crystallinity) and would convert to Mesylate Form 5 at 40°C./75% RH (and remained as Mesylate Form 3 at 25° C./97% RH). MesylateForm 4 was a metastable trihydrate that converted to Mesylate Form 1 at25° C./97% RH and was a mixture of Mesylate Form 1 and Form 4 after 1week at 40° C./75% RH. A fourth hydrate was then identified and isolatedduring an initial attempt to prepare the monohydrate. This new hydrate,Mesylate Form 5 was a hygroscopic sesquihydrate that was stable afterGVS analysis and remained as Mesylate Form 5 after 1 week at theelevated temperature/humidity conditions.

The thermodynamic solubility of the anhydrous Mesylate Form 1 and fourhydrates was measured in FaSSIF, FeSSIF and FaSSGF media. The anhydrousForm 1 typically displayed the highest solubility (1.90 mg/ml—FaSSIF;0.34—FeSSIF; 21.0 mg/ml FaSSGF) of the forms except Form 4 (trihydrate)which had slightly higher solubility in FaSSGF (24.0 mg/ml). Thesolubility residues in most cases showed disproportionation of the saltto FreeForm A, although two new solubility residue patterns wereidentified in FaSSGF from Mesylate Form 3 and Form 5, respectively.There was insufficient residue to characterize these further.

Competitive slurries of the anhydrous and hydrated forms in differentwater activity at 50° C. and 5° C. were used to determine thethermodynamic stability relationships. Mesylate Form 1 was the moststable up to aw =0.6 at 50° C. and up to at least aw=0.3 at 5° C. Basedon the solid form properties, thermodynamic aqueous solubility andunderstanding of the thermodynamic stability relationships between theseforms it was recommended to proceed to initial crystallizationdevelopment of the anhydrous Mesylate Form 1.

1.-20. (canceled)
 21. Crystalline mesylate Form 1 salt of N-hydroxy2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide.22. The crystalline mesylate of claim 21, characterized by an X-raydiffraction pattern reflection at a 2 theta value of 3.7°±0.3.
 23. Thecrystalline form of claim 22, further characterized by an X-raydiffraction pattern reflection at a 2 theta value of 14.9°±0.3.
 24. Thecrystalline mesylate of claim 22, further characterized by an X-raydiffraction pattern reflection at a 2 theta value of 7.5°±0.3.
 25. Thecrystalline mesylate of claim 23, further characterized by an X-raydiffraction pattern reflection at a 2 theta value of 7.5°±0.3.
 26. Thecrystalline mesylate of claim 22, further characterized by at least oneX-ray diffraction pattern reflection selected from a 2 theta value of7.5°±0.3, 14.9°±0.3, 17.3°±0.3, 19.7°±0.3, 22.5°±0.3, 22.9°±0.3, or30.1°±0.3.
 27. The crystalline mesylate of claim 22, furthercharacterized by at least two X-ray diffraction pattern reflectionsselected from a 2 theta value of 7.5°±0.3, 14.9°±0.3, 17.3°±0.3,19.7°±0.3, 22.5°±0.3, 22.9°±0.3, or 30.1°±0.3.
 28. The crystallinemesylate of claim 22, further characterized by at least three X-raydiffraction pattern reflections selected from a 2 theta value of7.5°±0.3, 14.9°±0.3, 17.3°±0.3, 19.7°±0.3, 22.5°±0.3, 22.9°±0.3, or30.1°±0.3.
 29. The crystalline mesylate of claim 22, furthercharacterized by at least four X-ray diffraction pattern reflectionsselected from a 2 theta value of 7.5°±0.3, 14.9°±0.3, 17.3°±0.3,19.7°±0.3, 22.5°±0.3, 22.9°±0.3, or 30.1°±0.3.
 30. The crystallinemesylate of claim 22, further characterized by at least five X-raydiffraction pattern reflections selected from a 2 theta value of7.5°±0.3, 14.9°±0.3, 17.3°±0.3, 19.7°±0.3, 22.5°±0.3, 22.9°±0.3, or30.1°±0.3.
 31. The crystalline mesylate of claim 21, characterized bythe X-ray powder diffraction pattern as shown in FIG. 1 .
 32. Thecrystalline mesylate of claim 21, characterized by thermogravimetricanalysis (TGA), wherein the TGA thermogram exhibits less than 0.5%±0.5weight loss up to 225° C.±10.0.
 33. The crystalline mesylate of claim21, characterized by the thermogravimetric analysis (TGA) pattern asshown in FIG. 3 .
 34. The crystalline mesylate of claim 21,characterized by differential scanning calorimetry (DSC), wherein theDSC thermogram exhibits a single exothermic event with an onsettemperature at about 222.1° C.±5.0 (433 J/g) or an exothermic peak at225.8° C. ±5.0.
 35. The crystalline mesylate of claim 21, characterizedby the differential scanning calorimetry (DSC) pattern as shown in FIG.3 .
 36. The crystalline mesylate of claim 21, wherein the amount ofanother crystalline form or an amorphous form is 5% (w/w) or less. 37.The crystalline mesylate of claim 21, wherein the crystalline mesylateis substantially free of impurities.
 38. A pharmaceutical compositioncomprising the crystalline form of claim 21, and one or morepharmaceutically acceptable excipients or carriers.
 39. Thepharmaceutical composition of claim 38, further comprising one or moreadditional active pharmaceutical ingredient (API).
 40. Thepharmaceutical composition of claim 39, wherein the additional API isvalganciclovir.